DOCETAXEL- docetaxel injection, solution Sandoz Inc.----------

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use DOCETAXEL INJECTIONsafely and effectively. See full prescribing information for DOCETAXEL INJECTION.

DOCETAXEL INJECTION, for intravenous useInitial U.S. Approval: 1996

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITYREACTIONS, and FLUID RETENTION

See full prescribing information for complete boxed warning.

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RECENT MAJOR CHANGES

INDICATIONS AND USAGEDocetaxel Injection is a microtubule inhibitor indicated for:

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DOSAGE AND ADMINISTRATIONAdminister in a facility equipped to manage possible complications (e.g., anaphylaxis). Administerintravenously (IV) over 1 hour every 3 weeks. PVC equipment is not recommended.

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Treatment-related mortality increases with abnormal liver function, at higherdoses, and in patients with NSCLC and prior platinum-based therapy receivingdocetaxel at 100 mg/m (5.1)2

Avoid use of docetaxel if bilirubin > ULN, or if AST and/or ALT > 1.5 × ULNconcomitant with alkaline phosphatase > 2.5 × ULN. LFT elevations increase risk ofsevere or life-threatening complications. Obtain LFTs before each treatment cycle(5.2)Do not administer docetaxel to patients with neutrophil counts < 1500 cells/mm .Obtain frequent blood counts to monitor for neutropenia (4, 5.3)

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Severe hypersensitivity, including fatal anaphylaxis, has been reported in patientswho received dexamethasone premedication. Severe reactions require immediatediscontinuation of Docetaxel Injection and administration of appropriate therapy(5.5)Contraindicated if history of severe hypersensitivity reactions to docetaxel or todrugs formulated with polysorbate 80 (4)Severe fluid retention may occur despite dexamethasone (5.6)

Warnings and Precautions (5.14) 01/2021

Breast Cancer (BC): single agent for locally advanced or metastatic BC after chemotherapy failure;and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC (1.1)Non-Small Cell Lung Cancer (NSCLC): single agent for locally advanced or metastatic NSCLCafter platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastaticuntreated NSCLC (1.2)Castration-Resistant Prostate Cancer (CRPC): with prednisone in metastatic castration-resistant prostate cancer (1.3)Gastric Adenocarcinoma (GC): with cisplatin and fluorouracil for untreated, advanced GC,including the gastroesophageal junction (1.4)Squamous Cell Carcinoma of the Head and Neck (SCCHN): with cisplatin and fluorouracil forinduction treatment of locally advanced SCCHN (1.5)

BC locally advanced or metastatic: 60 mg/m to 100 mg/m single agent (2.1)2 2

BC adjuvant: 75 mg/m administered 1 hour after doxorubicin 50 mg/m and cyclophosphamide 500mg/m every 3 weeks for 6 cycles (2.1)

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NSCLC: after platinum therapy failure: 75 mg/m single agent (2.2)2

NSCLC: chemotherapy-naive: 75 mg/m followed by cisplatin 75 mg/m (2.2)2 2

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For all patients:

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DOSAGE FORMS AND STRENGTHS

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CONTRAINDICATIONS

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WARNINGS AND PRECAUTIONS

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ADVERSE REACTIONSMost common adverse reactions across all docetaxel indications are infections, neutropenia, anemia,febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation,anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia,skin reactions, and myalgia. (6)To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc., at 1-800-525-8747 or FDAat 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

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USE IN SPECIFIC POPULATIONS

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See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.Revised: 1/2021

NSCLC: chemotherapy-naive: 75 mg/m followed by cisplatin 75 mg/m (2.2)CRPC: 75 mg/m with 5 mg prednisone twice a day continuously (2.3)2

GC: 75 mg/m followed by cisplatin 75 mg/m (both on day 1 only) followed by fluorouracil 750 mg/mper day as a 24-hr IV (days 1-5), starting at end of cisplatin infusion (2.4)

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SCCHN: 75 mg/m followed by cisplatin 75 mg/m IV (day 1), followed by fluorouracil 750 mg/m perday as a 24-hr IV (days 1-5), starting at end of cisplatin infusion; for 4 cycles (2.5)

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SCCHN: 75 mg/m followed by cisplatin 100 mg/m IV (day 1), followed by fluorouracil 1000 mg/m perday as a 24-hr IV (days 1-4); for 3 cycles (2.5)

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Pre-medicate with oral corticosteroids (2.6)Adjust dose as needed (2.7)

Multiple-dose vial 20 mg/2 mL, 80 mg/8 mL and 160 mg/16 mL (3)

Hypersensitivity to docetaxel or polysorbate 80 (4)Neutrophil counts of <1500 cells/mm (4)3

Second primary malignancies: In patients treated with docetaxel-containing regimens, monitor fordelayed AML, MDS, NHL, and renal cancer. (5.7)Cutaneous reactions: Reactions including erythema of the extremities with edema followed bydesquamation may occur. Severe cutaneous adverse reactions have been reported. Severe skintoxicity may require dose adjustment or permanent treatment discontinuation. (5.8)Neurologic reactions: Reactions including paresthesia, dysesthesia, and pain may occur. Severeneurosensory symptoms require dose adjustment or discontinuation if persistent. (5.9)Eye disorders: Cystoid macular edema (CME) has been reported and requires treatmentdiscontinuation. (5.10)Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.11)Embryo-fetal toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to useeffective contraception. (5.12, 8.1, 8.3)Alcohol content: The alcohol content in a dose of Docetaxel Injection may affect the central nervoussystem. This may include impairment of a patient’s ability to drive or use machines immediately afterinfusion. (5.13)Tumor lysis syndrome: Tumor lysis syndrome has been reported. Patients at risk should be wellhydrated and closely monitored during treatment. (5.14)

Cytochrome P450 3A4 inducers, inhibitors, or substrates: May alter docetaxel metabolism. (7)

Lactation: Advise women not to breastfeed. (8.2)Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation ofDocetaxel Injection. (8.3)

FULL PRESCRIBING INFORMATION: CONTENTS*WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA,HYPERSENSITIVITY REACTIONS, and FLUID RETENTION1. INDICATIONS AND USAGE

1.1 Breast Cancer1.2 Non-Small Cell Lung Cancer1.3 Prostate Cancer1.4 Gastric Adenocarcinoma1.5 Head and Neck Cancer

2. DOSAGE AND ADMINISTRATION2.1 Breast Cancer2.2 Non-Small Cell Lung Cancer2.3 Prostate Cancer2.4 Gastric Adenocarcinoma2.5 Head and Neck Cancer2.6 Premedication Regimen2.7 Dosage Adjustments During Treatment2.8 Administration Precautions2.9 Preparation and Administration2.10 Stability

3. DOSAGE FORMS AND STRENGTHS4. CONTRAINDICATIONS5. WARNINGS AND PRECAUTIONS

5.1 Toxic Deaths5.2 Hepatic Impairment5.3 Hematologic Effects5.4 Enterocolitis and Neutropenic Colitis5.5 Hypersensitivity Reactions5.6 Fluid Retention5.7 Second Primary Malignancies5.8 Cutaneous Reactions5.9 Neurologic Reactions5.10 Eye Disorders5.11 Asthenia5.12 Embryo-Fetal Toxicity5.13 Alcohol Content5.14 Tumor Lysis Syndrome

6. ADVERSE REACTIONS6.1 Clinical Trials Experience6.2 Postmarketing Experience

7. DRUG INTERACTIONS8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy8.2 Lactation8.3 Females and Males of Reproductive Potential8.4 Pediatric Use8.5 Geriatric Use8.6 Hepatic Impairment

10. OVERDOSAGE11. DESCRIPTION12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action12.3 Pharmacokinetics

13. NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14. CLINICAL STUDIES14.1 Locally Advanced or Metastatic Breast Cancer14.2 Adjuvant Treatment of Breast Cancer14.3 Non-Small Cell Lung Cancer (NSCLC)14.4 Castration-Resistant Prostate Cancer14.5 Gastric Adenocarcinoma14.6 Head and Neck Cancer

15. REFERENCES16. HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied16.2 Storage16.3 Handling and Disposal

17. PATIENT COUNSELING INFORMATION*

FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA,HYPERSENSITIVITY REACTIONS, and FLUID RETENTION

Treatment-related mortality associated with docetaxel is increased inpatients with abnormal liver function, in patients receiving higher doses,and in patients with non-small cell lung carcinoma and a history of priortreatment with platinum-based chemotherapy who receive docetaxel asa single agent at a dose of 100 mg/m [see Warnings and Precautions(5.1)].Avoid the use of Docetaxel Injection in patients with bilirubin > upperlimit of normal (ULN), or to patients with AST and/or ALT >1.5 x ULNconcomitant with alkaline phosphatase >2.5 x ULN. Patients withelevations of bilirubin or abnormalities of transaminase concurrent withalkaline phosphatase are at increased risk for the development ofsevere neutropenia, febrile neutropenia, infections, severethrombocytopenia, severe stomatitis, severe skin toxicity, and toxicdeath. Patients with isolated elevations of transaminase >1.5 x ULN alsohad a higher rate of febrile neutropenia. Measure bilirubin, AST or ALT,and alkaline phosphatase prior to each cycle of Docetaxel Injection [seeWarnings and Precautions (5.2)].Do not administer Docetaxel Injection to patients with neutrophil countsof <1500 cells/mm . Monitor blood counts frequently as neutropeniamay be severe and result in infection [see Warnings and Precautions(5.3)].Do not administer Docetaxel Injection to patients who have a history ofsevere hypersensitivity reactions to Docetaxel Injection or to otherdrugs formulated with polysorbate 80 [see Contraindications (4)].Severe hypersensitivity reactions have been reported in patientsdespite dexamethasone premedication. Hypersensitivity reactionsrequire immediate discontinuation of the Docetaxel Injection infusion andadministration of appropriate therapy [see Warnings and Precautions(5.5)].Severe fluid retention occurred in 6.5% (6/92) of patients despite use ofdexamethasone premedication. It was characterized by one or more ofthe following events: poorly tolerated peripheral edema, generalizededema, pleural effusion requiring urgent drainage, dyspnea at rest,cardiac tamponade, or pronounced abdominal distention (due to ascites)[see Warnings and Precautions (5.6)].

1. INDICATIONS AND USAGE

1.1 Breast CancerDocetaxel Injection is indicated for the treatment of patients with locally advanced ormetastatic breast cancer after failure of prior chemotherapy.Docetaxel Injection in combination with doxorubicin and cyclophosphamide is indicated

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for the adjuvant treatment of patients with operable node-positive breast cancer.

1.2 Non-Small Cell Lung CancerDocetaxel Injection as a single agent is indicated for the treatment of patients with locallyadvanced or metastatic non-small cell lung cancer after failure of prior platinum-basedchemotherapy.Docetaxel Injection in combination with cisplatin is indicated for the treatment of patientswith unresectable, locally advanced or metastatic non-small cell lung cancer who havenot previously received chemotherapy for this condition.

1.3 Prostate CancerDocetaxel Injection in combination with prednisone is indicated for the treatment ofpatients with metastatic castration-resistant prostate cancer.

1.4 Gastric AdenocarcinomaDocetaxel Injection in combination with cisplatin and fluorouracil is indicated for thetreatment of patients with advanced gastric adenocarcinoma, including adenocarcinomaof the gastroesophageal junction, who have not received prior chemotherapy foradvanced disease.

1.5 Head and Neck CancerDocetaxel Injection in combination with cisplatin and fluorouracil is indicated for theinduction treatment of patients with locally advanced squamous cell carcinoma of thehead and neck (SCCHN).

2. DOSAGE AND ADMINISTRATIONFor all indications, toxicities may warrant dosage adjustments [see Dosage andAdministration (2.7)].

Administer in a facility equipped to manage possible complications (e.g., anaphylaxis).

2.1 Breast Cancer

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2.2 Non-Small Cell Lung Cancer

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For locally advanced or metastatic breast cancer after failure of priorchemotherapy, the recommended dose of Docetaxel Injection is 60 mg/m to 100mg/m administered intravenously over 1 hour every 3 weeks.

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For the adjuvant treatment of operable node-positive breast cancer, therecommended Docetaxel Injection dose is 75 mg/m administered 1 hour afterdoxorubicin 50 mg/m and cyclophosphamide 500 mg/m every 3 weeks for 6courses. Prophylactic G-CSF may be used to mitigate the risk of hematologicaltoxicities [see Dosage and Administration (2.7)].

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For treatment after failure of prior platinum-based chemotherapy, docetaxel wasevaluated as monotherapy, and the recommended dose is 75 mg/m administeredintravenously over 1 hour every 3 weeks. A dose of 100 mg/m in patients

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2.3 Prostate CancerFor metastatic castration-resistant prostate cancer, the recommended dose ofDocetaxel Injection is 75 mg/m every 3 weeks as a 1 hour intravenous infusion.Prednisone 5 mg orally twice daily is administered continuously [see Dosage andAdministration (2.7)].

2.4 Gastric AdenocarcinomaFor gastric adenocarcinoma, the recommended dose of Docetaxel Injection is 75 mg/mas a 1-hour intravenous infusion, followed by cisplatin 75 mg/m , as a 1- to 3- hourintravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m per daygiven as a 24-hour continuous intravenous infusion for 5 days, starting at the end of thecisplatin infusion. Treatment is repeated every three weeks. Patients must receivepremedication with antiemetics and appropriate hydration for cisplatin administration[see Dosage and Administration (2.7)].

2.5 Head and Neck CancerPatients must receive premedication with antiemetics, and appropriate hydration (priorto and after cisplatin administration). Prophylaxis for neutropenic infections should beadministered. All patients treated on the docetaxel injection containing arms of theTAX323 and TAX324 studies received prophylactic antibiotics.Induction Chemotherapy Followed by Radiotherapy (TAX323)

Induction Chemotherapy Followed by Chemoradiotherapy (TAX324)

previously treated with chemotherapy was associated with increased hematologictoxicity, infection, and treatment-related mortality in randomized, controlled trials[see Boxed Warning, Dosage and Administration (2.7), Warnings and Precautions(5), Clinical Studies (14)].For chemotherapy-naive patients, docetaxel was evaluated in combination withcisplatin. The recommended dose of Docetaxel Injection is 75 mg/m administeredintravenously over 1 hour immediately followed by cisplatin 75 mg/m over 30-60minutes every 3 weeks [see Dosage and Administration (2.7)].

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For the induction treatment of locally advanced inoperable SCCHN, therecommended dose of Docetaxel Injection is 75 mg/m as a 1-hour intravenousinfusion followed by cisplatin 75 mg/m intravenously over 1 hour, on day one,followed by fluorouracil as a continuous intravenous infusion at 750 mg/m per dayfor five days. This regimen is administered every 3 weeks for 4 cycles. Followingchemotherapy, patients should receive radiotherapy [see Dosage andAdministration (2.7)].

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For the induction treatment of patients with locally advanced (unresectable, lowsurgical cure, or organ preservation) SCCHN, the recommended dose of DocetaxelInjection is 75 mg/m as a 1-hour intravenous infusion on day 1, followed bycisplatin 100 mg/m administered as a 30-minute to 3 hour infusion, followed byfluorouracil 1000 mg/m /day as a continuous infusion from day 1 to day 4. Thisregimen is administered every 3 weeks for 3 cycles. Following chemotherapy,patients should receive chemoradiotherapy [see Dosage and Administration (2.7)].

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2.6 Premedication RegimenAll patients should be premedicated with oral corticosteroids (see below for prostatecancer) such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 daysstarting 1 day prior to Docetaxel Injection administration in order to reduce the incidenceand severity of fluid retention as well as the severity of hypersensitivity reactions [seeBoxed Warning, Warnings and Precautions (5.5)].

For metastatic castration-resistant prostate cancer, given the concurrent use ofprednisone, the recommended premedication regimen is oral dexamethasone 8 mg, at12 hours, 3 hours and 1 hour before the Docetaxel Injection infusion [see Warnings andPrecautions (5.5)].

2.7 Dosage Adjustments During TreatmentBreast CancerPatients who are dosed initially at 100 mg/m and who experience either febrileneutropenia, neutrophils <500 cells/mm for more than 1 week, or severe or cumulativecutaneous reactions during Docetaxel Injection therapy should have the dosageadjusted from 100 mg/m to 75 mg/m . If the patient continues to experience thesereactions, the dosage should either be decreased from 75 mg/m to 55 mg/m or thetreatment should be discontinued. Conversely, patients who are dosed initially at 60mg/m and who do not experience febrile neutropenia, neutrophils <500 cells/mm formore than 1 week, severe or cumulative cutaneous reactions, or severe peripheralneuropathy during Docetaxel Injection therapy may tolerate higher doses. Patients whodevelop ≥grade 3 peripheral neuropathy should have Docetaxel Injection treatmentdiscontinued entirely.Combination Therapy with Docetaxel Injection in the Adjuvant Treatment ofBreast CancerDocetaxel Injection in combination with doxorubicin and cyclophosphamide should beadministered when the neutrophil count is ≥1,500 cells/mm . Patients who experiencefebrile neutropenia should receive G-CSF in all subsequent cycles. Patients who continueto experience this reaction should remain on G-CSF and have their Docetaxel Injectiondose reduced to 60 mg/m . Patients who experience grade 3 or 4 stomatitis shouldhave their Docetaxel Injection dose decreased to 60 mg/m . Patients who experiencesevere or cumulative cutaneous reactions or moderate neurosensory signs and/orsymptoms during Docetaxel Injection therapy should have their dosage of DocetaxelInjection reduced from 75 mg/m to 60 mg/m . If the patient continues to experiencethese reactions at 60 mg/m , treatment should be discontinued.Non-Small Cell Lung CancerMonotherapy with Docetaxel Injection for NSCLC treatment after failure of priorplatinum-based chemotherapy

Patients who are dosed initially at 75 mg/m and who experience either febrileneutropenia, neutrophils <500 cells/mm for more than one week, severe or cumulativecutaneous reactions, or other grade 3/4 non-hematological toxicities during DocetaxelInjection treatment should have treatment withheld until resolution of the toxicity andthen resumed at 55 mg/m . Patients who develop ≥grade 3 peripheral neuropathyshould have Docetaxel Injection treatment discontinued entirely.

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Combination therapy with Docetaxel Injection for chemotherapy-naive NSCLC

For patients who are dosed initially at Docetaxel Injection 75 mg/m in combination withcisplatin, and whose nadir of platelet count during the previous course of therapy is<25,000 cells/mm , in patients who experience febrile neutropenia, and in patients withserious non-hematologic toxicities, the Docetaxel Injection dosage in subsequent cyclesshould be reduced to 65 mg/m . In patients who require a further dose reduction, adose of 50 mg/m is recommended. For cisplatin dosage adjustments, seemanufacturers' prescribing information.Prostate CancerCombination therapy with Docetaxel Injection for metastatic castration-resistant prostatecancer

Docetaxel Injection should be administered when the neutrophil count is ≥1,500cells/mm . Patients who experience either febrile neutropenia, neutrophils <500cells/mm for more than one week, severe or cumulative cutaneous reactions ormoderate neurosensory signs and/or symptoms during Docetaxel Injection therapyshould have the dosage of Docetaxel Injection reduced from 75 mg/m to 60 mg/m . Ifthe patient continues to experience these reactions at 60 mg/m , the treatment shouldbe discontinued.Gastric or Head and Neck CancerDocetaxel Injection in combination with cisplatin and fluorouracil in gastric cancer or headand neck cancer

Patients treated with Docetaxel Injection in combination with cisplatin and fluorouracilmust receive antiemetics and appropriate hydration according to current institutionalguidelines. In both studies, G-CSF was recommended during the second and/orsubsequent cycles in case of febrile neutropenia, or documented infection withneutropenia, or neutropenia lasting more than 7 days. If an episode of febrileneutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use,the Docetaxel Injection dose should be reduced from 75 mg/m to 60 mg/m . Ifsubsequent episodes of complicated neutropenia occur the Docetaxel Injection doseshould be reduced from 60 mg/m to 45 mg/m . In case of grade 4 thrombocytopeniathe Docetaxel Injection dose should be reduced from 75 mg/m to 60 mg/m . Do notretreat patients with subsequent cycles of Docetaxel Injection until neutrophils recoverto a level >1,500 cells/mm [see Contraindications (4)]. Avoid retreating patients untilplatelets recover to a level >100,000 cells/mm . Discontinue treatment if these toxicitiespersist [see Warnings and Precautions (5.3)].

Recommended dose modifications for toxicities in patients treated with DocetaxelInjection in combination with cisplatin and fluorouracil are shown in Table 1.Table 1 - Recommended Dose Modifications for Toxicities in Patients Treatedwith Docetaxel Injection in Combination with Cisplatin and Fluorouracil

Toxicity Dosage AdjustmentDiarrhea grade 3 First episode: reduce fluorouracil dose by 20%.

Second episode: then reduce Docetaxel Injection dose by20%.

Diarrhea grade 4 First episode: reduce Docetaxel Injection and fluorouracil

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doses by 20%.Second episode: discontinue treatment.

Stomatitis/mucositis grade3

First episode: reduce fluorouracil dose by 20%.Second episode: stop fluorouracil only, at all subsequentcycles.Third episode: reduce Docetaxel Injection dose by 20%.

Stomatitis/mucositis grade4

First episode: stop fluorouracil only, at all subsequent cycles.Second episode: reduce Docetaxel Injection dose by 20%.

Liver dysfunction:In case of AST/ALT >2.5 to ≤5 × ULN and AP ≤2.5 × ULN, or AST/ALT >1.5 to ≤5 ×ULN and AP >2.5 to ≤5 × ULN, Docetaxel Injection should be reduced by 20%.In case of AST/ALT >5 × ULN and/or AP >5 × ULN Docetaxel Injection should bestopped.The dose modifications for cisplatin and fluorouracil in the gastric cancer study areprovided below:Cisplatin dose modifications and delaysPeripheral neuropathy: A neurological examination should be performed before entryinto the study, and then at least every 2 cycles and at the end of treatment. In the caseof neurological signs or symptoms, more frequent examinations should be performedand the following dose modifications can be made according to NCI-CTCAE grade:

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Ototoxicity: In the case of grade 3 toxicity, discontinue treatment.Nephrotoxicity: In the event of a rise in serum creatinine ≥grade 2 (>1.5 × normalvalue) despite adequate rehydration, CrCl should be determined before each subsequentcycle and the following dose reductions should be considered (see Table 2).For other cisplatin dosage adjustments, also refer to the manufacturers’ prescribinginformation.Table 2 - Dose Reductions for Evaluation of Creatinine Clearance

CreatinineClearance ResultBefore Next Cycle

Cisplatin Dose Next Cycle

CrCl ≥60 mL/min Full dose of cisplatin was given.CrCl was to be repeated beforeeach treatment cycle.

CrCl between 40 and59 mL/min

Dose of cisplatin was reduced by50% at subsequent cycle. If CrClwas >60 mL/min at end of cycle,full cisplatin dose was reinstitutedat the next cycle.If no recovery was observed, then

Grade 2: Reduce cisplatin dose by 20%.Grade 3: Discontinue treatment.

cisplatin was omitted from thenext treatment cycle.

CrCl <40 mL/min Dose of cisplatin was omitted inthat treatment cycle only.If CrCl was still <40 mL/min at theend of cycle, cisplatin wasdiscontinued.If CrCl was >40 and <60 mL/minat end of cycle, a 50% cisplatindose was given at the next cycle.If CrCl was >60 mL/min at end ofcycle, full cisplatin dose was givenat next cycle.

CrCl = Creatinine clearance

Fluorouracil dose modifications and treatment delaysFor diarrhea and stomatitis, see Table 1.In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stoppeduntil recovery. The fluorouracil dosage should be reduced by 20%.For other greater than grade 3 toxicities, except alopecia and anemia, chemotherapyshould be delayed (for a maximum of 2 weeks from the planned date of infusion) untilresolution to grade ≤1 and then recommenced, if medically appropriate.For other fluorouracil dosage adjustments, also refer to the manufacturers’ prescribinginformation.Combination Therapy with Strong CYP3A4 Inhibitors:Avoid using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole,clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,telithromycin and voriconazole). There are no clinical data with a dose adjustment inpatients receiving strong CYP3A4 inhibitors. Based on extrapolation from apharmacokinetic study with ketoconazole in 7 patients, consider a 50% docetaxel dosereduction if patients require co-administration of a strong CYP3A4 inhibitor [see DrugInteractions (7), Clinical Pharmacology (12.3)].

2.8 Administration PrecautionsDocetaxel Injection is a cytotoxic anticancer drug and, as with other potentially toxiccompounds, caution should be exercised when handling and preparing DocetaxelInjection solutions. The use of gloves is recommended [see How Supplied/Storage andHandling (16.3)].

If Docetaxel Injection or diluted solution for intravenous infusion should come intocontact with the skin, immediately and thoroughly wash with soap and water. IfDocetaxel Injection or diluted solution for intravenous infusion should come into contactwith mucosa, immediately and thoroughly wash with water.Contact of the Docetaxel Injection with plasticized PVC equipment or devices used toprepare solutions for infusion is not recommended. In order to minimize patientexposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from

PVC infusion bags or sets, the Docetaxel Injection diluted solution for infusion should bestored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) andadministered through polyethylene-lined administration sets.Docetaxel Injection requires NO prior dilution with a diluent and is ready to add to theinfusion solution. Please follow the preparation instructions provided below.

2.9 Preparation and AdministrationDilution for Infusion

The Docetaxel Injection diluted solution for infusion should be administered intravenouslyas a 1-hour infusion under ambient room temperature below 25°C (77°F) and lightingconditions.

2.10 StabilityDocetaxel Injection infusion solution, if stored between 2°C and 25°C (36°F and 77°F) isstable for 4 hours in either 0.9% Sodium Chloride solution or 5% Dextrose solution. Usewithin 4 hours including storage and administration. Do not freeze infusion solution.

3. DOSAGE FORMS AND STRENGTHS

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4. CONTRAINDICATIONSDocetaxel Injection is contraindicated in patients with:

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Using only a 21 gauge needle, aseptically withdraw the required amount ofDocetaxel Injection solution (10 mg docetaxel/mL) with a calibrated syringe andinject (as a single injection) into a 250 mL infusion bag or bottle of either 0.9%Sodium Chloride solution or 5% Dextrose solution to produce a final concentrationof 0.3 mg/mL to 0.74 mg/mL.If a dose greater than 200 mg of Docetaxel Injection is required, use a largervolume of the infusion vehicle so that a concentration of 0.74 mg/mL DocetaxelInjection is not exceeded.Thoroughly mix the infusion bag or bottle manually by gentle inversion and rotationin a controlled manner and avoid foaming. Shaking or vigorous agitation should beavoided during preparation and transportation to the patient for administration.As with all parenteral products, Docetaxel Injection should be inspected visually forparticulate matter or discoloration prior to administration whenever the solution andcontainer permit. If the Docetaxel Injection vial or diluted solution is not clear orappears to have precipitation, these should be discarded.

20 mg/2 mL multiple-dose vial80 mg/8 mL multiple-dose vial160 mg/16 mL multiple-dose vial

neutrophil counts of <1500 cells/mm [see Warnings and Precautions (5.3)].3a history of severe hypersensitivity reactions to docetaxel or to other drugsformulated with polysorbate 80. Severe reactions, including anaphylaxis, haveoccurred [see Warnings and Precautions (5.5)].

5. WARNINGS AND PRECAUTIONS

5.1 Toxic DeathsBreast CancerDocetaxel administered at 100 mg/m was associated with deaths considered possiblyor probably related to treatment in 2.0% (19/965) of metastatic breast cancer patients,both previously treated and untreated, with normal baseline liver function and in 11.5%(7/61) of patients with various tumor types who had abnormal baseline liver function(AST and/or ALT >1.5 times ULN together with AP >2.5 times ULN). Among patientsdosed at 60 mg/m , mortality related to treatment occurred in 0.6% (3/481) of patientswith normal liver function, and in 3 of 7 patients with abnormal liver function.Approximately half of these deaths occurred during the first cycle. Sepsis accounted forthe majority of the deaths.Non-Small Cell Lung CancerDocetaxel administered at a dose of 100 mg/m in patients with locally advanced ormetastatic non-small cell lung cancer who had a history of prior platinum-basedchemotherapy was associated with increased treatment-related mortality (14% and 5%in two randomized, controlled studies). There were 2.8% treatment-related deathsamong the 176 patients treated at the 75 mg/m dose in the randomized trials. Amongpatients who experienced treatment-related mortality at the 75 mg/m dose level, 3 of 5patients had an ECOG PS of 2 at study entry [see Dosage and Administration (2.2),Clinical Studies (14)].

5.2 Hepatic ImpairmentPatients with elevations of bilirubin or abnormalities of transaminase concurrent withalkaline phosphatase are at increased risk for the development of severe neutropenia,febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skintoxicity, and toxic death.Avoid docetaxel in patients with bilirubin > upper limit of normal (ULN), or to patientswith AST and/or ALT >1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN [seeWarnings and Precautions (5.1)].

For patients with isolated elevations of transaminase >1.5 x ULN, consider docetaxeldose modifications [see Dosage and Administration (2.7)].

Measure bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle of docetaxeltherapy.

5.3 Hematologic EffectsPerform frequent peripheral blood cell counts on all patients receiving DocetaxelInjection. Do not retreat patients with subsequent cycles of Docetaxel Injection untilneutrophils recover to a level >1500 cells/mm [see Contraindications (4)]. Avoidretreating patients until platelets recover to a level >100,000 cells/mm .A 25% reduction in the dose of Docetaxel Injection is recommended during subsequentcycles following severe neutropenia (<500 cells/mm ) lasting 7 days or more, febrile

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neutropenia, or a grade 4 infection in a Docetaxel Injection cycle [see Dosage andAdministration (2.7)].

Neutropenia (<2000 neutrophils/mm ) occurs in virtually all patients given 60 mg/m to100 mg/m of docetaxel and grade 4 neutropenia (<500 cells/mm ) occurs in 85% ofpatients given 100 mg/m and 75% of patients given 60 mg/m . Frequent monitoring ofblood counts is, therefore, essential so that dose can be adjusted. Docetaxel Injectionshould not be administered to patients with neutrophils <1500 cells/mm .Febrile neutropenia occurred in about 12% of patients given 100 mg/m but was veryuncommon in patients given 60 mg/m .Hematologic responses, febrile reactions and infections, and rates of septic death fordifferent regimens are dose related [see Adverse Reactions (6.1), Clinical Studies (14)].

Three breast cancer patients with severe liver impairment (bilirubin >1.7 times ULN)developed fatal gastrointestinal bleeding associated with severe drug-inducedthrombocytopenia. In gastric cancer patients treated with docetaxel in combination withcisplatin and fluorouracil (TCF), febrile neutropenia and/or neutropenic infection occurredin 12% of patients receiving G-CSF compared to 28% who did not. Patients receiving TCFshould be closely monitored during the first and subsequent cycles for febrileneutropenia and neutropenic infection [see Dosage and Administration (2.7), AdverseReactions (6)].

5.4 Enterocolitis and Neutropenic ColitisEnterocolitis and neutropenic colitis (typhlitis) have occurred in patients treated withdocetaxel alone and in combination with other chemotherapeutic agents, despite thecoadministration of G-CSF. Caution is recommended for patients with neutropenia,particularly at risk for developing gastrointestinal complications. Enterocolitis andneutropenic enterocolitis may develop at any time, and could lead to death as early asthe first day of symptom onset. Monitor patients closely from onset of any symptoms ofgastrointestinal toxicity. Inform patients to contact their healthcare provider with new,or worsening symptoms of gastrointestinal toxicity [see Dosage and Administration (2),Warnings and Precautions (5.3), Adverse Reactions (6.2)].

5.5 Hypersensitivity ReactionsMonitor patients closely for hypersensitivity reactions, especially during the first andsecond infusions. Severe hypersensitivity reactions characterized by generalizedrash/erythema, hypotension and/or bronchospasm, or fatal anaphylaxis, have beenreported in patients premedicated with 3 days of corticosteroids. Severe hypersensitivityreactions require immediate discontinuation of the Docetaxel Injection infusion andaggressive therapy. Do not rechallenge patients with a history of severe hypersensitivityreactions with Docetaxel Injection [see Contraindications (4)].

Patients who have previously experienced a hypersensitivity reaction to paclitaxel maydevelop a hypersensitivity reaction to docetaxel that may include severe or fatalreactions such as anaphylaxis. Monitor patients with a previous history ofhypersensitivity to paclitaxel closely during initiation of docetaxel therapy.Hypersensitivity reactions may occur within a few minutes following initiation of aDocetaxel Injection infusion. If minor reactions such as flushing or localized skinreactions occur, interruption of therapy is not required. All patients should be

3 22 3

2 2

3

22

premedicated with an oral corticosteroid prior to the initiation of the infusion ofDocetaxel Injection [see Dosage and Administration (2.6)].

5.6 Fluid RetentionSevere fluid retention has been reported following docetaxel therapy. Patients should bepremedicated with oral corticosteroids prior to each Docetaxel Injection administrationto reduce the incidence and severity of fluid retention [see Dosage and Administration(2.6)]. Patients with pre-existing effusions should be closely monitored from the firstdose for the possible exacerbation of the effusions.When fluid retention occurs, peripheral edema usually starts in the lower extremities andmay become generalized with a median weight gain of 2 kg.Among 92 breast cancer patients premedicated with 3-day corticosteroids, moderatefluid retention occurred in 27.2% and severe fluid retention in 6.5%. The mediancumulative dose to onset of moderate or severe fluid retention was 819 mg/m . Nine of92 patients (9.8%) of patients discontinued treatment due to fluid retention: 4 patientsdiscontinued with severe fluid retention; the remaining 5 had mild or moderate fluidretention. The median cumulative dose to treatment discontinuation due to fluidretention was 1021 mg/m .Fluid retention was completely, but sometimes slowly, reversible with a median of 16weeks from the last infusion of docetaxel to resolution (range: 0 to 42+ weeks). Patientsdeveloping peripheral edema may be treated with standard measures, e.g., saltrestriction, oral diuretic(s).

5.7 Second Primary MalignanciesSecond primary malignancies, notably acute myeloid leukemia (AML), myelodysplasticsyndrome (MDS), Non-Hodgkin’s Lymphoma (NHL), and renal cancer, have beenreported in patients treated with docetaxel-containing regimens. These adversereactions may occur several months or years after docetaxel-containing therapy.Treatment-related AML or MDS has occurred in patients given anthracyclines and/orcyclophosphamide, including use in adjuvant therapy for breast cancer. In the adjuvantbreast cancer trial (TAX316) AML occurred in 3 of 744 patients who received docetaxel,doxorubicin and cyclophosphamide (TAC) and in 1 of 736 patients who receivedfluorouracil, doxorubicin and cyclophosphamide [see Clinical Studies (14.2)]. In TAC-treated patients, the risk of delayed myelodysplasia or myeloid leukemia requireshematological follow-up. Monitor patients for second primary malignancies [see AdverseReactions (6.1)].

5.8 Cutaneous ReactionsLocalized erythema of the extremities with edema followed by desquamation has beenobserved. In case of severe skin toxicity, an adjustment in dosage is recommended [seeDosage and Administration (2.7)]. The discontinuation rate due to skin toxicity was 1.6%(15/965) for metastatic breast cancer patients. Among 92 breast cancer patientspremedicated with 3-day corticosteroids, there were no cases of severe skin toxicityreported and no patient discontinued docetaxel due to skin toxicity.Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS),toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis

2

2

(AGEP) have been reported in association with docetaxel treatment. Patients should beinformed about the signs and symptoms of serious skin manifestations and monitoredclosely. Permanent treatment discontinuation should be considered in patients whoexperience SCARs.

5.9 Neurologic ReactionsSevere neurosensory symptoms (e.g., paresthesia, dysesthesia, pain) were observed in5.5% (53/965) of metastatic breast cancer patients and resulted in treatmentdiscontinuation in 6.1%. When these symptoms occur, dosage must be adjusted. Ifsymptoms persist, treatment should be discontinued [see Dosage and Administration(2.7)]. Patients who experienced neurotoxicity in clinical trials and for whom follow-upinformation on the complete resolution of the event was available had spontaneousreversal of symptoms with a median of 9 weeks from onset (range: 0 to 106 weeks).Severe peripheral motor neuropathy mainly manifested as distal extremity weaknessoccurred in 4.4% (42/965).

5.10 Eye DisordersCystoid macular edema (CME) has been reported in patients treated with docetaxel.Patients with impaired vision should undergo a prompt and comprehensiveophthalmologic examination. If CME is diagnosed, docetaxel treatment should bediscontinued and appropriate treatment initiated. Alternative non-taxane cancertreatment should be considered.

5.11 AstheniaSevere asthenia has been reported in 14.9% (144/965) of metastatic breast cancerpatients but has led to treatment discontinuation in only 1.8%. Symptoms of fatigue andweakness may last a few days up to several weeks and may be associated withdeterioration of performance status in patients with progressive disease.

5.12 Embryo-Fetal ToxicityBased on findings from animal reproduction studies and its mechanism of action,docetaxel can cause fetal harm when administered to a pregnant woman [see ClinicalPharmacology (12.1)]. Available data from case reports in the literature andpharmacovigilance with docetaxel use in pregnant women are not sufficient to informthe drug-associated risk of major birth defects, miscarriage or adverse maternal or fetaloutcomes. In animal reproduction studies, administration of docetaxel to pregnant ratsand rabbits during the period of organogenesis caused embryo-fetal toxicities, includingintrauterine mortality, at doses as low as 0.02 and 0.003 times the recommendedhuman dose based on body surface area, respectively.Advise pregnant women and females of reproductive potential of the potential risk to afetus. Verify pregnancy status in females of reproductive potential prior to initiatingdocetaxel. Advise females of reproductive potential to use effective contraception duringtreatment and for 6 months after the last dose of Docetaxel Injection. Advise malepatients with female partners of reproductive potential to use effective contraceptionduring treatment and for 3 months after the last dose of Docetaxel Injection [see Use inSpecific Populations (8.1, 8.3)].

5.13 Alcohol ContentCases of intoxication have been reported with some formulations of docetaxel due tothe alcohol content. The alcohol content in a dose of Docetaxel Injection may affect thecentral nervous system and should be taken into account for patients in whom alcoholintake should be avoided or minimized. Consideration should be given to the alcoholcontent in Docetaxel Injection on the ability to drive or use machines immediately afterthe infusion. Each administration of Docetaxel Injection at 100 mg/m delivers 2.65 g/mof ethanol. For a patient with a BSA of 2.0 m , this would deliver 5.3 grams of ethanol[see Description (11)]. Other docetaxel products may have a different amount ofalcohol.

5.14 Tumor Lysis SyndromeTumor lysis syndrome has been reported with docetaxel [see Adverse Reactions (6.2)].Patients at risk of tumor lysis syndrome (e.g., with renal impairment, hyperuricemia,bulky tumor) should be closely monitored prior to initiating Docetaxel Injection andperiodically during treatment. Correction of dehydration and treatment of high uric acidlevels are recommended prior to initiation of treatment.

6. ADVERSE REACTIONSThe most serious adverse reactions from docetaxel are:

••••••••••••

The most common adverse reactions across all docetaxel indications are infections,neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia,neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention,asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, andmyalgia. Incidence varies depending on the indication. Adverse reactions are describedaccording to indication. Because clinical trials are conducted under widely varyingconditions, adverse reaction rates observed in the clinical trials of a drug cannot bedirectly compared to rates in the clinical trials of another drug and may not reflect therates observed in practice.Responding patients may not experience an improvement in performance status ontherapy and may experience worsening. The relationship between changes inperformance status, response to therapy, and treatment-related side effects has notbeen established.

2 22

Toxic Deaths [see Boxed Warning, Warnings and Precautions (5.1)]Hepatic Impairment [see Boxed Warning, Warnings and Precautions (5.2)]Hematologic Effects [see Boxed Warning, Warnings and Precautions (5.3)]Enterocolitis and Neutropenic Colitis [see Warnings and Precautions (5.4)]Hypersensitivity Reactions [see Boxed Warning, Warnings and Precautions (5.5)]Fluid Retention [see Boxed Warning, Warnings and Precautions (5.6)]Second Primary Malignancies [see Warnings and Precautions (5.7)]Cutaneous Reactions [see Warnings and Precautions (5.8)]Neurologic Reactions [see Warnings and Precautions (5.9)]Eye Disorders [see Warnings and Precautions (5.10)]Asthenia [see Warnings and Precautions (5.11)]Alcohol Content [see Warnings and Precautions (5.13)]

6.1 Clinical Trials ExperienceBreast CancerMonotherapy with docetaxel for locally advanced or metastatic breast cancer afterfailure of prior chemotherapy

Docetaxel 100 mg/m : Adverse drug reactions occurring in at least 5% of patients arecompared for three populations who received docetaxel administered at 100 mg/m as a1-hour infusion every 3 weeks: 2045 patients with various tumor types and normalbaseline liver function tests; the subset of 965 patients with locally advanced ormetastatic breast cancer, both previously treated and untreated with chemotherapy,who had normal baseline liver function tests; and an additional 61 patients with varioustumor types who had abnormal liver function tests at baseline. These reactions weredescribed using COSTART terms and were considered possibly or probably related todocetaxel. At least 95% of these patients did not receive hematopoietic support. Thesafety profile is generally similar in patients receiving docetaxel for the treatment ofbreast cancer and in patients with other tumor types (see Table 3).Table 3 - Summary of Adverse Reactions in Patients Receiving Docetaxel at100 mg/m

AllTumorTypes

AllTumorTypes

BreastCancer

NormalLFTs

ElevatedLFTs

NormalLFTs

AdverseReaction

n=2045%

n=61%

n=965%

HematologicNeutropenia<2000 cells/mm 96 96 99<500 cells/mm 75 88 86Leukopenia<4000 cells/mm 96 98 99<1000 cells/mm 32 47 44Thrombocytopenia<100,000cells/mm

8 25 9

Anemia<11 g/dL 90 92 94<8 g/dL 9 31 8FebrileNeutropenia

11 26 12

Septic Death 2 5 1Non-SepticDeath

1 7 1

InfectionsAny 22 33 22

22

2

* † *

33

33

3

‡

Severe 6 16 6Fever inAbsence ofInfectionAny 31 41 35Severe 2 8 2HypersensitivityReactionsRegardless ofPremedicationAny 21 20 18Severe 4 10 3With 3-dayPremedication

n=92 n=3 n=92

Any 15 33 15Severe 2 0 2Fluid RetentionRegardless ofPremedicationAnySevereWith 3-dayPremedicationAnySevere

477

n=92

647

398

n=3

6733

609

n=92

647

NeurosensoryAnySevere

494

340

586

CutaneousAnySevere

485

5410

475

Nail ChangesAnySevere

313

235

414

GastrointestinalNauseaVomitingDiarrheaSevere

3922395

3823335

4223436

StomatitisAnySevere

426

4913

527

Alopecia 76 62 74AstheniaAnySevere

6213

5325

6615

Myalgia

*

†

‡

AnySevere

192

162

212

Arthralgia 9 7 8Infusion SiteReactions

4 3 4

Hematologic ReactionsReversible marrow suppression was the major dose-limiting toxicity of docetaxel [seeWarnings and Precautions (5.3)]. The median time to nadir was 7 days, while the medianduration of severe neutropenia (<500 cells/mm ) was 7 days. Among 2045 patients withsolid tumors and normal baseline LFTs, severe neutropenia occurred in 75.4% andlasted for more than 7 days in 2.9% of cycles.Febrile neutropenia (<500 cells/mm with fever >38°C with intravenous antibioticsand/or hospitalization) occurred in 11% of patients with solid tumors, in 12.3% ofpatients with metastatic breast cancer, and in 9.8% of 92 breast cancer patientspremedicated with 3-day corticosteroids.Severe infectious episodes occurred in 6.1% of patients with solid tumors, in 6.4% ofpatients with metastatic breast cancer, and in 5.4% of 92 breast cancer patientspremedicated with 3-day corticosteroids.Thrombocytopenia (<100,000 cells/mm ) associated with fatal gastrointestinalhemorrhage has been reported.Hypersensitivity ReactionsSevere hypersensitivity reactions have been reported [see Boxed Warning, Warningsand Precautions (5.5)]. Minor events, including flushing, rash with or without pruritus,chest tightness, back pain, dyspnea, drug fever, or chills, have been reported andresolved after discontinuing the infusion and instituting appropriate therapy.Fluid RetentionFluid retention can occur with the use of docetaxel [see Boxed Warning, Dosage andAdministration (2.6), Warnings and Precautions (5.6)].

Cutaneous ReactionsSevere skin toxicity is discussed elsewhere in the label [see Warnings and Precautions(5.8)]. Reversible cutaneous reactions characterized by a rash including localizederuptions, mainly on the feet and/or hands, but also on the arms, face, or thorax,usually associated with pruritus, have been observed. Eruptions generally occurredwithin 1 week after docetaxel infusion, recovered before the next infusion, and were notdisabling.

Normal Baseline LFTs: Transaminases ≤1.5 timesULN or alkaline phosphatase ≤2.5 times ULN orisolated elevations of transaminases or alkalinephosphatase up to 5 times ULN.Elevated Baseline LFTs: AST and/or ALT >1.5times ULN concurrent with alkaline phosphatase>2.5 times ULN.Febrile Neutropenia: ANC grade 4 with fever>38°C with intravenous antibiotics and/orhospitalization.

3

3

3

Severe nail disorders were characterized by hypo- or hyperpigmentation, andoccasionally by onycholysis (in 0.8% of patients with solid tumors) and pain.Neurologic ReactionsNeurologic reactions are discussed elsewhere in the label [see Warnings and Precautions(5.9)].

Gastrointestinal ReactionsNausea, vomiting, and diarrhea were generally mild to moderate. Severe reactionsoccurred in 3% - 5% of patients with solid tumors and to a similar extent amongmetastatic breast cancer patients. The incidence of severe reactions was 1% or less forthe 92 breast cancer patients premedicated with 3-day corticosteroids.Severe stomatitis occurred in 5.5% of patients with solid tumors, in 7.4% of patientswith metastatic breast cancer, and in 1.1% of the 92 breast cancer patientspremedicated with 3-day corticosteroids.Cardiovascular ReactionsHypotension occurred in 2.8% of patients with solid tumors; 1.2% required treatment.Clinically meaningful events such as heart failure, sinus tachycardia, atrial flutter,dysrhythmia, unstable angina, pulmonary edema, and hypertension have occurred.Seven of 86 (8.1%) of metastatic breast cancer patients receiving docetaxel 100 mg/min a randomized trial and who had serial left ventricular ejection fractions assesseddeveloped deterioration of LVEF by ≥10% associated with a drop below the institutionallower limit of normal.Infusion Site ReactionsInfusion site reactions were generally mild and consisted of hyperpigmentation,inflammation, redness or dryness of the skin, phlebitis, extravasation, or swelling of thevein.Hepatic ReactionsIn patients with normal LFTs at baseline, bilirubin values greater than the ULN occurredin 8.9% of patients. Increases in AST or ALT >1.5 times the ULN, or alkalinephosphatase >2.5 times ULN, were observed in 18.9% and 7.3% of patients,respectively. While on docetaxel, increases in AST and/or ALT >1.5 times ULNconcomitant with alkaline phosphatase >2.5 times ULN occurred in 4.3% of patientswith normal LFTs at baseline. Whether these changes were related to the drug orunderlying disease has not been established.Hematologic and Other Toxicity: Relation to dose and baseline liver chemistryabnormalitiesHematologic and other toxicity is increased at higher doses and in patients with elevatedbaseline liver function tests (LFTs). In the following tables, adverse drug reactions arecompared for three populations: 730 patients with normal LFTs given docetaxel at 100mg/m in the randomized and single arm studies of metastatic breast cancer afterfailure of previous chemotherapy; 18 patients in these studies who had abnormalbaseline LFTs (defined as AST and/or ALT >1.5 times ULN concurrent with alkalinephosphatase >2.5 times ULN); and 174 patients in Japanese studies given docetaxel at60 mg/m who had normal LFTs (see Tables 4 and 5).

2

2

2

Table 4 - Hematologic Adverse Reactions in Breast Cancer PatientsPreviously Treated with Chemotherapy Treated at Docetaxel 100 mg/m withNormal or Elevated Liver Function Tests or 60 mg/m with Normal LiverFunction Tests

*

†

‡

§

Adverse Reaction Docetaxel 100mg/m

Docetaxel60 mg/m

NormalLFTsn=730

%

ElevatedLFTsn=18

%

Normal LFTs n=174

%NeutropeniaAny <2000cells/mm

98 100 95

Grade 4 <500cells/mm

84 94 75

ThrombocytopeniaAny <100,000cells/mm

11 44 14

Grade 4 <20,000cells/mm

1 17 1

Anemia <11 g/dL 95 94 65InfectionAny 23 39 1Grade 3 and 4 7 33 0FebrileNeutropeniaBy Patient 12 33 0By Course 2 9 0Septic Death 2 6 1Non-Septic Death 1 11 0

Table 5 - Non-Hematologic Adverse Reactions in Breast Cancer PatientsPreviously Treated with Chemotherapy Treated at Docetaxel 100 mg/m with

22

Normal Baseline LFTs: Transaminases ≤1.5 times ULNor alkaline phosphatase ≤2.5 times ULN or isolatedelevations of transaminases or alkaline phosphatase upto 5 times ULN.Elevated Baseline LFTs: AST and/or ALT >1.5 timesULN concurrent with alkaline phosphatase >2.5 timesULN.Incidence of infection requiring hospitalization and/orintravenous antibiotics was 8.5% (n=62) among the730 patients with normal LFTs at baseline; 7 patientshad concurrent grade 3 neutropenia, and 46 patientshad grade 4 neutropenia.Febrile Neutropenia: For 100 mg/m , ANC grade 4 andfever >38°C with intravenous antibiotics and/orhospitalization; for 60 mg/m , ANC grade 3/4 and fever>38.1°C.

2

2

2 2

* † *

3

3

3

3

‡

§

22

Normal or Elevated Liver Function Tests or 60 mg/m with Normal LiverFunction Tests

*

†

‡

AdverseReaction

Docetaxel 100mg/m

Docetaxel60 mg/m

NormalLFTsn=730

%

ElevatedLFTs n=18

%

NormalLFTsn=174

%AcuteHypersensitivityReactionRegardless ofPremedicationAny 13 6 1Severe 1 0 0Fluid RetentionRegardless ofPremedicationAny 56 61 13Severe 8 17 0NeurosensoryAny 57 50 20Severe 6 0 0Myalgia 23 33 3CutaneousAny 45 61 31Severe 5 17 0AstheniaAny 65 44 66Severe 17 22 0DiarrheaAny 42 28 NASevere 6 11StomatitisAny 53 67 19Severe 8 39 1NA = not available

2

Normal Baseline LFTs: Transaminases ≤1.5 timesULN or alkaline phosphatase ≤2.5 times ULN orisolated elevations of transaminases or alkalinephosphatase up to 5 times ULN.Elevated Baseline Liver Function: AST and/or ALT>1.5 times ULN concurrent with alkalinephosphatase >2.5 times ULN.Fluid Retention includes (by COSTART): edema(peripheral, localized, generalized, lymphedema,pulmonary edema, and edema otherwise notspecified) and effusion (pleural, pericardial, and

2

2 2

* † *

‡

In the three-arm monotherapy trial, TAX313, which compared docetaxel 60 mg/m , 75mg/m and 100 mg/m in advanced breast cancer, grade 3/4 or severe adversereactions occurred in 49.0% of patients treated with docetaxel 60 mg/m compared to55.3% and 65.9% treated with 75 mg/m and 100 mg/m respectively. Discontinuationdue to adverse reactions was reported in 5.3% of patients treated with 60 mg/mversus 6.9% and 16.5% for patients treated at 75 mg/m and 100 mg/m respectively.Deaths within 30 days of last treatment occurred in 4.0% of patients treated with 60mg/m compared to 5.3% and 1.6% for patients treated at 75 mg/m and 100 mg/mrespectively.The following adverse reactions were associated with increasing docetaxel doses: fluidretention (26%, 38%, and 46% at 60 mg/m , 75 mg/m , and 100 mg/m respectively),thrombocytopenia (7%, 11% and 12% respectively), neutropenia (92%, 94%, and 97%respectively), febrile neutropenia (5%, 7%, and 14% respectively), treatment-relatedgrade 3/4 infection (2%, 3%, and 7% respectively) and anemia (87%, 94%, and 97%respectively).Combination therapy with docetaxel in the adjuvant treatment of breastcancerThe following table presents treatment emergent adverse reactions observed in 744patients, who were treated with docetaxel 75 mg/m every 3 weeks in combination withdoxorubicin and cyclophosphamide (see Table 6).Table 6 - Clinically Important Treatment Emergent Adverse ReactionsRegardless of Causal Relationship in Patients Receiving Docetaxel inCombination with Doxorubicin and Cyclophosphamide (TAX316)

Docetaxel 75mg/m +

Doxorubicin 50mg/m +

Cyclophosphamide500

mg/m (TAC)n=744

%

Fluorouracil 500mg/m +

Doxorubicin 50mg/m +

Cyclophosphamide500 mg/m (FAC)

n=736%

Adverse Reaction Any Grade 3/4 Any Grade 3/4Anemia 92 4 72 2Neutropenia 71 66 82 49Fever in absenceof infection

47 1 17 0

Infection 39 4 36 2Thrombocytopenia 39 2 28 1Febrileneutropenia

25 N/A 3 N/A

Neutropenic 12 N/A 6 N/A

ascites); no premedication given with the 60 mg/mdose.

2

22 2

22 2

22 2

2 2 2

2 2 2

2

2

2

2

2

2

2

*

infectionHypersensitivityreactions

13 1 4 0

Lymphedema 4 0 1 0Fluid RetentionPeripheral edemaWeight gain

352713

100

1579

000

Neuropathysensory

26 0 10 0

Neuro-cortical 5 1 6 1Neuropathy motor 4 0 2 0Neuro-cerebellar 2 0 2 0Syncope 2 1 1 0Alopecia 98 N/A 97 N/ASkin toxicity 27 1 18 0Nail disorders 19 0 14 0Nausea 81 5 88 10Stomatitis 69 7 53 2Vomiting 45 4 59 7Diarrhea 35 4 28 2Constipation 34 1 32 1Taste perversion 28 1 15 0Anorexia 22 2 18 1Abdominal Pain 11 1 5 0Amenorrhea 62 N/A 52 N/ACough 14 0 10 0Cardiacdysrhythmias

8 0 6 0

Vasodilatation 27 1 21 1Hypotension 2 0 1 0Phlebitis 1 0 1 0Asthenia 81 11 71 6Myalgia 27 1 10 0Arthralgia 19 1 9 0Lacrimationdisorder

11 0 7 0

Conjunctivitis 5 0 7 0

Of the 744 patients treated with TAC, 36.3% experienced severe treatment emergentadverse reactions compared to 26.6% of the 736 patients treated with FAC. Dosereductions due to hematologic toxicity occurred in 1% of cycles in the TAC arm versus0.1% of cycles in the FAC arm. Six percent of patients treated with TAC discontinuedtreatment due to adverse reactions, compared to 1.1% treated with FAC; fever in theabsence of infection and allergy being the most common reasons for withdrawal amongTAC-treated patients. Two patients died in each arm within 30 days of their last studytreatment; 1 death per arm was attributed to study drugs.

COSTART term and grading system for events related to treatment.

*

treatment; 1 death per arm was attributed to study drugs.Fever and InfectionDuring the treatment period, fever in the absence of infection was seen in 46.5% ofTAC-treated patients and in 17.1% of FAC-treated patients. Grade 3/4 fever in theabsence of infection was seen in 1.3% and 0% of TAC- and FAC-treated patientsrespectively. Infection was seen in 39.4% of TAC-treated patients compared to 36.3% ofFAC-treated patients. Grade 3/4 infection was seen in 3.9% and 2.2% of TAC-treated andFAC-treated patients respectively. There were no septic deaths in either treatment armduring the treatment period.Gastrointestinal ReactionsIn addition to gastrointestinal reactions reflected in the table above, 7 patients in the TACarm were reported to have colitis/enteritis/large intestine perforation versus one patientin the FAC arm. Five of the 7 TAC-treated patients required treatment discontinuation; nodeaths due to these events occurred during the treatment period.Cardiovascular ReactionsMore cardiovascular reactions were reported in the TAC arm versus the FAC arm duringthe treatment period: arrhythmias, all grades (6.2% vs. 4.9%), and hypotension, allgrades (1.9% vs. 0.8%). Twenty-six (26) patients (3.5%) in the TAC arm and 17 patients(2.3%) in the FAC arm developed CHF during the study period. All except one patient ineach arm were diagnosed with CHF during the follow-up period. Two (2) patients in TACarm and 4 patients in FAC arm died due to CHF. The risk of CHF was higher in the TACarm in the first year, and then was similar in both treatment arms.Adverse reactions during the follow-up period (median follow-up time of 8years)In study TAX316, the most common adverse reactions that started during thetreatment period and persisted into the follow-up period in TAC and FAC patients aredescribed below (median follow-up time of 8 years).Nervous system disordersIn study TAX316, peripheral sensory neuropathy started during the treatment periodand persisted into the follow-up period in 84 patients (11.3%) in TAC arm and 15patients (2%) in FAC arm. At the end of the follow-up period (median follow-up time of 8years), peripheral sensory neuropathy was observed to be ongoing in 10 patients(1.3%) in TAC arm, and in 2 patients (0.3%) in FAC arm.Skin and subcutaneous tissue disordersIn study TAX316, alopecia persisting into the follow-up period after the end ofchemotherapy was reported in 687 of 744 TAC patients (92.3%) and 645 of 736 FACpatients (87.6%). At the end of the follow-up period (actual median follow-up time of 8years), alopecia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FACpatients (2.2%).Reproductive system and breast disordersIn study TAX316, amenorrhea that started during the treatment period and persistedinto the follow-up period after the end of chemotherapy was reported in 202 of 744 TACpatients (27.2%) and 125 of 736 FAC patients (17.0%). Amenorrhea was observed to beongoing at the end of the follow-up period (median follow-up time of 8 years) in 121 of

744 TAC patients (16.3%) and 86 FAC patients (11.7%).General disorders and administration site conditionsIn study TAX316, peripheral edema that started during the treatment period andpersisted into the follow-up period after the end of chemotherapy was observed in 119of 744 TAC patients (16.0%) and 23 of 736 FAC patients (3.1%). At the end of thefollow-up period (actual median follow-up time of 8 years), peripheral edema wasongoing in 19 TAC patients (2.6%) and 4 FAC patients (0.5%).In study TAX316, lymphedema that started during the treatment period and persistedinto the follow-up period after the end of chemotherapy was reported in 11 of 744 TACpatients (1.5%) and 1 of 736 FAC patients (0.1%). At the end of the follow-up period(actual median follow-up time of 8 years), lymphedema was observed to be ongoing in 6TAC patients (0.8%) and 1 FAC patient (0.1%).In study TAX316, asthenia that started during the treatment period and persisted intothe follow-up period after the end of chemotherapy was reported in 236 of 744 TACpatients (31.7%) and 180 of 736 FAC patients (24.5%). At the end of the follow-upperiod (actual median follow-up time of 8 years), asthenia was observed to be ongoing in29 TAC patients (3.9%) and 16 FAC patients (2.2%).Acute Myeloid Leukemia (AML)/Myelodysplastic Syndrome (MDS)AML occurred in the adjuvant breast cancer trial (TAX316). The cumulative risk ofdeveloping treatment-related AML at median follow-up time of 8 years in TAX316 was0.4% for TAC-treated patients and 0.1% for FAC-treated patients. One TAC patient(0.1%) and 1 FAC patient (0.1%) died due to AML during the follow-up period (medianfollow-up time of 8 years). Myelodysplastic syndrome occurred in 2 of 744 (0.3%)patients who received TAC and in 1 of 736 (0.1%) patients who received FAC. AMLoccurs at a higher frequency when these agents are given in combination with radiationtherapy.Lung CancerMonotherapy with docetaxel for unresectable, locally advanced or metastatic NSCLCpreviously treated with platinum-based chemotherapy

Docetaxel 75 mg/m : Treatment-emergent adverse drug reactions are shown in Table 7.Included in this table are safety data for a total of 176 patients with non-small cell lungcarcinoma and a history of prior treatment with platinum-based chemotherapy whowere treated in two randomized, controlled trials. These reactions were described usingNCI Common Toxicity Criteria regardless of relationship to study treatment, except forthe hematologic toxicities or where otherwise noted.Table 7 - Treatment Emergent Adverse Reactions Regardless of Relationshipto Treatment in Patients Receiving Docetaxel as Monotherapy for Non-SmallCell Lung Cancer Previously Treated with Platinum-Based Chemotherapy*

Adverse ReactionDocetaxel75 mg/m

n=176%

BestSupportive

Caren=49

%

Vinorelbine/Ifosfamide

n=119%

2

2

NeutropeniaAnyGrade 3/4

8465

1412

8357

LeukopeniaAnyGrade 3/4

8449

60

8943

ThrombocytopeniaAnyGrade 3/4

83

00

82

AnemiaAnyGrade 3/4

919

5512

9114

FebrileNeutropenia

6 NA 1

InfectionAnyGrade 3/4

3410

296

309

TreatmentRelated Mortality

3 NA 3

HypersensitivityReactionsAnyGrade 3/4

63

00

10

Fluid RetentionAnySevere

343

ND 233

NeurosensoryAnyGrade 3/4

232

146

295

NeuromotorAnyGrade 3/4

165

86

103

SkinAnyGrade 3/4

201

62

171

GastrointestinalNauseaAny 34 31 31Grade 3/4 5 4 8VomitingAny 22 27 22Grade 3/4 3 2 6DiarrheaAny 23 6 12Grade 3/4 3 0 4Alopecia 56 35 50AstheniaAny 53 57 54

†§

§

¶

Any 53 57 54Severe 18 39 23StomatitisAny 26 6 8Grade 3/4 2 0 1PulmonaryAny 41 49 45Grade 3/4 21 29 19Nail DisorderAny 11 0 2Severe 1 0 0MyalgiaAny 6 0 3Severe 0 0 0ArthralgiaAny 3 2 2Severe 0 0 1Taste PerversionAny 6 0 0Severe 1 0 0* Normal Baseline LFTs: Transaminases ≤1.5 times ULN oralkaline phosphatase ≤2.5 times ULN or isolated elevationsof transaminases or alkaline phosphatase up to 5 timesULN.† Febrile Neutropenia: ANC grade 4 with fever >38°C withintravenous antibiotics and/or hospitalization.‡ COSTART term and grading system.§ Not Applicable¶ Not Done

Combination therapy with docetaxel in chemotherapy-naive advanced unresectable ormetastatic NSCLC

Table 8 presents safety data from two arms of an open label, randomized controlled trial(TAX326) that enrolled patients with unresectable stage IIIB or IV non-small cell lungcancer and no history of prior chemotherapy. Adverse reactions were described usingthe NCI Common Toxicity Criteria except where otherwise noted.Table 8 - Adverse Reactions Regardless of Relationship to Treatment inChemotherapy-Naive Advanced Non-Small Cell Lung Cancer PatientsReceiving Docetaxel in Combination with Cisplatin

Adverse Reaction Docetaxel75 mg/m

+Cisplatin

75 mg/mn=406

%

Vinorelbine25 mg/m+ Cisplatin100 mg/m

n=396%

‡

‡

‡

‡

‡

2

2

2

2

NeutropeniaAny 91 90Grade 3/4 74 78FebrileNeutropenia

5 5

ThrombocytopeniaAny 15 15Grade 3/4 3 4AnemiaAny 89 94Grade 3/4 7 25InfectionAny 35 37Grade 3/4 8 8Fever in absenceof infectionAny 33 29Grade 3/4 <1 1HypersensitivityReactionAny 12 4Grade 3/4 3 <1Fluid RetentionAny 54 42All severe or life-threatening events

2 2

Pleural effusionAny 23 22All severe or life-threatening events

2 2

Peripheral edemaAny 34 18All severe or life-threatening events

<1 <1

Weight gainAny 15 9All severe or life-threatening events

<1 <1

NeurosensoryAny 47 42Grade 3/4 4 4NeuromotorAny 19 17Grade 3/4 3 6SkinAny 16 14

*

†

*†

Grade 3/4 <1 1NauseaAny 72 76Grade 3/4 10 17VomitingAny 55 61Grade 3/4 8 16DiarrheaAny 47 25Grade 3/4 7 3AnorexiaAny 42 40All severe or life-threatening events

5 5

StomatitisAny 24 21Grade 3/4 2 1AlopeciaAny 75 42Grade 3 <1 0AstheniaAny 74 75All severe or life-threatening events

12 14

Nail DisorderAny 14 <1All severe events <1 0MyalgiaAny 18 12All severe events <1 <1

Deaths within 30 days of last study treatment occurred in 31 patients (7.6%) in thedocetaxel+cisplatin arm and 37 patients (9.3%) in the vinorelbine+cisplatin arm. Deathswithin 30 days of last study treatment attributed to study drug occurred in 9 patients(2.2%) in the docetaxel+cisplatin arm and 8 patients (2%) in the vinorelbine+cisplatinarm.The second comparison in the study, vinorelbine+cisplatin versus docetaxel+carboplatin(which did not demonstrate a superior survival associated with docetaxel, [see ClinicalStudies (14.3)] demonstrated a higher incidence of thrombocytopenia, diarrhea, fluidretention, hypersensitivity reactions, skin toxicity, alopecia and nail changes on thedocetaxel+carboplatin arm, while a higher incidence of anemia, neurosensory toxicity,nausea, vomiting, anorexia and asthenia was observed on the vinorelbine+cisplatin arm.Prostate Cancer

Replaces NCI term "Allergy".COSTART term and grading system

†

†

†

†

Combination therapy with docetaxel in patients with prostate cancer

The following data are based on the experience of 332 patients, who were treated withdocetaxel 75 mg/m every 3 weeks in combination with prednisone 5 mg orally twicedaily (see Table 9).Table 9- Clinically Important Treatment-Emergent Adverse Reactions(Regardless of Relationship) in Patients with Prostate Cancer Who ReceivedDocetaxel in Combination with Prednisone (TAX327)

Docetaxel75 mg/mevery 3weeks +

prednisone5 mg twice

dailyn=332

%

Mitoxantrone12 mg/mevery 3weeks +

prednisone 5mg twice

dailyn=335

%Adverse Reaction Any Grade

3/4Any Grade

3/4Anemia 67 5 58 2Neutropenia 41 32 48 22Thrombocytopenia 3 1 8 1Febrile Neutropenia 3 N/A 2 N/AInfection 32 6 20 4Epistaxis 6 0 2 0Allergic Reactions 8 1 1 0Fluid RetentionWeight GainPeripheral Edema

24818

100

532

000

Neuropathy Sensory 30 2 7 0Neuropathy Motor 7 2 3 1Rash/Desquamation 6 0 3 1Alopecia 65 N/A 13 N/ANail Changes 30 0 8 0Nausea 41 3 36 2Diarrhea 32 2 10 1Stomatitis/Pharyngitis 20 1 8 0Taste Disturbance 18 0 7 0Vomiting 17 2 14 2Anorexia 17 1 14 0Cough 12 0 8 0Dyspnea 15 3 9 1Cardiac leftventricular function

10 0 22 1

Fatigue 53 5 35 5Myalgia 15 0 13 1

2

2 2

**

*

*

Tearing 10 1 2 0Arthralgia 8 1 5 1

Gastric CancerCombination therapy with docetaxel injection in gastric adenocarcinoma

Data in the following table are based on the experience of 221 patients with advancedgastric adenocarcinoma and no history of prior chemotherapy for advanced disease,who were treated with docetaxel injection 75 mg/m in combination with cisplatin andfluorouracil (see Table 10).Table 10 - Clinically Important Treatment-Emergent Adverse ReactionsRegardless of Relationship to Treatment in the Gastric Cancer Study

DocetaxelInjection75 mg/m+ cisplatin75 mg/m

+fluorouracil750 mg/m

n=221

Cisplatin100 mg/m

+fluorouracil

1000mg/mn=224

Adverse Reaction Any%

Grade3/4%

Any%

Grade3/4%

Anemia 97 18 93 26Neutropenia 96 82 83 57Fever in the absenceof infection

36 2 23 1

Thrombocytopenia 26 8 39 14Infection 29 16 23 10Febrile neutropenia 16 N/A 5 N/ANeutropenic infection 16 N/A 10 N/AAllergic reactions 10 2 6 0Fluid retention 15 0 4 0Edema 13 0 3 0Lethargy 63 21 58 18Neurosensory 38 8 25 3Neuromotor 9 3 8 3Dizziness 16 5 8 2Alopecia 67 5 41 1Rash/itch 12 1 9 0Nail changes 8 0 0 0Skin desquamation 2 0 0 0Nausea 73 16 76 19

Related to treatment.

2

2

2

2

2

2

**

*

Vomiting 67 15 73 19Anorexia 51 13 54 12Stomatitis 59 21 61 27Diarrhea 78 20 50 8Constipation 25 2 34 3Esophagitis/dysphagia/odynophagia

16 2 14 5

Gastrointestinalpain/cramping

11 2 7 3

Cardiac dysrhythmias 5 2 2 1Myocardial ischemia 1 0 3 2Tearing 8 0 2 0Altered hearing 6 0 13 2Clinically important treatment-emergent adversereactions were determined based upon frequency,severity, and clinical impact of the adverse reaction.

Head and Neck CancerCombination therapy with docetaxel injection in head and neck cancer

Table 11 summarizes the safety data obtained from patients that received inductionchemotherapy with docetaxel injection 75 mg/m in combination with cisplatin andfluorouracil followed by radiotherapy (TAX323; 174 patients) or chemoradiotherapy(TAX324; 251 patients). The treatment regimens are described in Section 14.6.Table 11 - Clinically Important Treatment-Emergent Adverse Reactions(Regardless of Relationship) in Patients with SCCHN Receiving InductionChemotherapy with Docetaxel Injection in Combination with Cisplatin andFluorouracil Followed by Radiotherapy (TAX323) or Chemoradiotherapy(TAX324)

TAX323(n=355)

TAX324(n=494)

DocetaxelInjection

arm(n=174)

Comparatorarm

(n=181)

DocetaxelInjection

arm(n=251)

Comparatorarm

(n=243)

Adverse Reaction(by Body System)

Any%

Grade3/4 %

Any%

Grade3/4 %

Any%

Grade3/4 %

Any%

Grade3/4 %

Neutropenia 93 76 87 53 95 84 84 56Anemia 89 9 88 14 90 12 86 10Thrombocytopenia 24 5 47 18 28 4 31 11Infection 27 9 26 8 23 6 28 5Febrile neutropenia 5 N/A 2 N/A 12 N/A 7 N/ANeutropenic infection 14 N/A 8 N/A 12 N/A 8 N/ACancer pain 21 5 16 3 17 9 20 11

Related to treatment.

2

*

*

†‡

Lethargy 41 3 38 3 61 5 56 10Fever in the absenceof infection

32 1 37 0 30 4 28 3

Myalgia 10 1 7 0 7 0 7 2Weight loss 21 1 27 1 14 2 14 2Allergy 6 0 3 0 2 0 0 0Fluid retentionEdema onlyWeight gain only

20136

000

1476

100

13120

110

761

210

Dizziness 2 0 5 1 16 4 15 2Neurosensory 18 1 11 1 14 1 14 0Altered hearing 6 0 10 3 13 1 19 3Neuromotor 2 1 4 1 9 0 10 2Alopecia 81 11 43 0 68 4 44 1Rash/itch 12 0 6 0 20 0 16 1Dry skin 6 0 2 0 5 0 3 0Desquamation 4 1 6 0 2 0 5 0Nausea 47 1 51 7 77 14 80 14Stomatitis 43 4 47 11 66 21 68 27Vomiting 26 1 39 5 56 8 63 10Diarrhea 33 3 24 4 48 7 40 3Constipation 17 1 16 1 27 1 38 1Anorexia 16 1 25 3 40 12 34 12Esophagitis/dysphagia/Odynophagia

13 1 18 3 25 13 26 10

Taste, sense of smellaltered

10 0 5 0 20 0 17 1

Gastrointestinalpain/cramping

8 1 9 1 15 5 10 2

Heartburn 6 0 6 0 13 2 13 1Gastrointestinalbleeding

4 2 0 0 5 1 2 1

Cardiac dysrhythmia 2 2 2 1 6 3 5 3Venous 3 2 6 2 4 2 5 4Ischemia myocardial 2 2 1 0 2 1 1 1Tearing 2 0 1 0 2 0 2 0Conjunctivitis 1 0 1 0 1 0 0.4 0Clinically important treatment-emergent adverse reactions based uponfrequency, severity, and clinical impact.

6.2 Postmarketing ExperienceThe following adverse reactions have been identified from clinical trials and/orpostmarketing surveillance. Because these reactions are reported from a population of

Febrile neutropenia: grade ≥2 fever concomitant with grade 4 neutropenia requiringintravenous antibiotics and/or hospitalization.Related to treatment.Includes superficial and deep vein thrombosis and pulmonary embolism.

†

‡

uncertain size, it is not always possible to reliably estimate their frequency or establish acausal relationship to drug exposure.Body as a whole: diffuse pain, chest pain, radiation recall phenomenon, injection siterecall reaction (recurrence of skin reaction at a site of previous extravasation followingadministration of docetaxel at a different site) at the site of previous extravasation.Cardiovascular: atrial fibrillation, deep vein thrombosis, ECG abnormalities,thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction.Ventricular arrhythmia including ventricular tachycardia, in patients treated withdocetaxel in combination regimens including doxorubicin, 5-fluorouracil and/orcyclophosphamide, may be associated with fatal outcome.Cutaneous: cutaneous lupus erythematosus, bullous eruptions such as erythemamultiforme and severe cutaneous adverse reactions (SCARs) such as Stevens-Johnsonsyndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis,scleroderma-like changes (usually preceded by peripheral lymphedema), severe palmar-plantar erythrodysesthesia and permanent alopecia.Gastrointestinal: enterocolitis, including colitis, ischemic colitis, and neutropenicenterocolitis, which may be fatal. Abdominal pain, anorexia, constipation, duodenal ulcer,esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, intestinalobstruction, ileus, and dehydration as a consequence of gastrointestinal events.Hearing: ototoxicity, hearing disorders and/or hearing loss, including during use withother ototoxic drugs.Hematologic: bleeding episodes, disseminated intravascular coagulation (DIC), often inassociation with sepsis or multiorgan failure.Hepatic: hepatitis, sometimes fatal, primarily in patients with pre-existing liver disorders.Hypersensitivity: anaphylactic shock with fatal outcome in patients who receivedpremedication. Severe hypersensitivity reactions with fatal outcome with docetaxel inpatients who previously experienced hypersensitivity reactions to paclitaxel.Metabolism and Nutrition Disorders: electrolyte imbalance, including hyponatremia,hypokalemia, hypomagnesemia, and hypocalcemia. Tumor lysis syndrome, sometimesfatal.Neurologic: confusion, seizures or transient loss of consciousness, sometimesappearing during the infusion of the drug.Ophthalmologic: conjunctivitis, lacrimation or lacrimation with or without conjunctivitis,cystoid macular edema (CME). Excessive tearing which may be attributable to lacrimalduct obstruction. Transient visual disturbances (flashes, flashing lights, scotomata)typically occurring during drug infusion and reversible upon discontinuation of theinfusion, in association with hypersensitivity reactions.Respiratory: dyspnea, acute pulmonary edema, acute respiratory distresssyndrome/pneumonitis, interstitial lung disease, interstitial pneumonia, respiratoryfailure, and pulmonary fibrosis, which may be fatal. Radiation pneumonitis in patientsreceiving concomitant radiotherapy.Renal: renal insufficiency and renal failure, the majority of cases were associated withconcomitant nephrotoxic drugs.

Second primary malignancies: second primary malignancies, including AML, MDS,NHL, and renal cancer [see Warnings and Precautions (5.7)].Musculoskeletal disorder: myositis.

7. DRUG INTERACTIONSDocetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism ofdocetaxel may be modified by the concomitant administration of compounds thatinduce, inhibit, or are metabolized by cytochrome P450 3A4.In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it wasco-administered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors,particularly ritonavir, may increase the exposure of docetaxel. Concomitant use ofDocetaxel Injection and drugs that inhibit CYP3A4 may increase exposure to docetaxeland should be avoided. In patients receiving treatment with Docetaxel Injection closemonitoring for toxicity and a Docetaxel Injection dose reduction could be considered ifsystemic administration of a potent CYP3A4 inhibitor cannot be avoided [see Dosage andAdministration (2.7), Clinical Pharmacology (12.3)].

8. USE IN SPECIFIC POPULATIONS

8.1 PregnancyRisk SummaryBased on findings in animal reproduction studies and its mechanism of action, DocetaxelInjection can cause fetal harm when administered to a pregnant woman [see ClinicalPharmacology (12.1)]. Available data from case reports in the literature andpharmacovigilance with docetaxel use in pregnant women are not sufficient to informthe drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetaloutcomes. Docetaxel Injection contains alcohol which can interfere with neurobehavioraldevelopment [see Clinical Considerations]. In animal reproductive studies, administrationof docetaxel to pregnant rats and rabbits during the period of organogenesis caused anincreased incidence of embryo-fetal toxicities, including intrauterine mortality, at dosesas low as 0.02 and 0.003 times the recommended human dose based on body surfacearea, respectively [see Data]. Advise pregnant women and females of reproductivepotential of the potential risk to a fetus.The estimated background risk of major birth defects and miscarriage for the indicatedpopulations is unknown. All pregnancies have a background risk of birth defect,miscarriage, or other adverse outcomes. In the U.S. general population, the estimatedbackground risk of major birth defects and miscarriage in clinically recognizedpregnancies is 2% to 4% and 15% to 20%, respectively.Clinical ConsiderationsDocetaxel Injection contains alcohol [see Warnings and Precautions (5.13)]. Publishedstudies have demonstrated that alcohol is associated with fetal harm including centralnervous system abnormalities, behavioral disorders, and impaired intellectualdevelopment.Data

DataAnimal data

Intravenous administration of ≥0.3 and 0.03 mg/kg/day docetaxel to pregnant rats andrabbits, respectively, during the period of organogenesis caused an increased incidenceof intrauterine mortality, resorptions, reduced fetal weights, and fetal ossification delays.Maternal toxicity was also observed at these doses, which were approximately 0.02 and0.003 times the daily maximum recommended human dose based on body surfacearea, respectively.

8.2 LactationRisk SummaryThere is no information regarding the presence of docetaxel in human milk, or on itseffects on milk production or the breastfed child. No lactation studies in animals havebeen conducted. Because of the potential for serious adverse reactions in a breastfedchild, advise women not to breastfeed during treatment with Docetaxel Injection and for1 week after the last dose.

8.3 Females and Males of Reproductive PotentialPregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating DocetaxelInjection.ContraceptionFemales

Docetaxel can cause fetal harm when administered to a pregnant woman [see Use inSpecific Populations (8.1)]. Advise females of reproductive potential to use effectivecontraception during treatment and for 6 months after the last dose of DocetaxelInjection.Males

Based on genetic toxicity findings, advise male patients with female partners ofreproductive potential to use effective contraception during treatment and for 3 monthsafter the last dose of Docetaxel Injection.InfertilityBased on findings in animal studies, Docetaxel Injection may impair fertility in males ofreproductive potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric UseThe alcohol content of Docetaxel Injection should be taken into account when given topediatric patients [see Warnings and Precautions(5.13)].The efficacy of docetaxel in pediatric patients as monotherapy or in combination has notbeen established. The overall safety profile of docetaxel in pediatric patients receivingmonotherapy or TCF was consistent with the known safety profile in adults.Docetaxel has been studied in a total of 289 pediatric patients: 239 in 2 trials withmonotherapy and 50 in combination treatment with cisplatin and 5-fluorouracil (TCF).

monotherapy and 50 in combination treatment with cisplatin and 5-fluorouracil (TCF).Docetaxel MonotherapyDocetaxel monotherapy was evaluated in a dose-finding phase 1 trial in 61 pediatricpatients (median age 12.5 years, range 1-22 years) with a variety of refractory solidtumors. The recommended dose was 125 mg/m as a 1-hour intravenous infusion every21 days. The primary dose limiting toxicity was neutropenia.The recommended dose for docetaxel monotherapy was evaluated in a phase 2 single-arm trial in 178 pediatric patients (median age 12 years, range 1-26 years) with a varietyof recurrent/refractory solid tumors. Efficacy was not established with tumor responserates ranging from one complete response (CR) (0.6%) in a patient with undifferentiatedsarcoma to four partial responses (2.2%) seen in one patient each with Ewing Sarcoma,neuroblastoma, osteosarcoma, and squamous cell carcinoma.Docetaxel in CombinationDocetaxel was studied in combination with cisplatin and 5-fluorouracil (TCF) versuscisplatin and 5-fluorouracil (CF) for the induction treatment of nasopharyngealcarcinoma (NPC) in pediatric patients prior to chemoradiation consolidation. Seventy-fivepatients (median age 16 years, range 9 to 21 years) were randomized (2:1) to docetaxel(75 mg/m ) in combination with cisplatin (75 mg/m ) and 5-fluorouracil (750 mg/m )(TCF) or to cisplatin (80 mg/m ) and 5-fluorouracil (1000 mg/m /day) (CF). The primaryendpoint was the CR rate following induction treatment of NPC. One patient out of 50 inthe TCF group (2%) had a complete response while none of the 25 patients in the CFgroup had a complete response.PharmacokineticsPharmacokinetic parameters for docetaxel were determined in 2 pediatric solid tumortrials. Following docetaxel administration at 55 mg/m to 235 mg/m in a 1-hourintravenous infusion every 3-weeks in 25 patients aged 1 to 20 years (median 11 years),docetaxel clearance was 17.3±10.9 L/h/m .Docetaxel was administered in combination with cisplatin and 5-fluorouracil (TCF), atdose levels of 75 mg/m in a 1-hour intravenous infusion day 1 in 28 patients aged 10 to21 years (median 16 years, 17 patients were older than 16). Docetaxel clearance was17.9±8.75 L/h/m , corresponding to an AUC of 4.20±2.57 µg•h/mL.In summary, the body surface area adjusted clearance of docetaxel monotherapy andTCF combination in children were comparable to those in adults [see ClinicalPharmacology (12.3)].

8.5 Geriatric UseIn general, dose selection for an elderly patient should be cautious, reflecting the greaterfrequency of decreased hepatic, renal, or cardiac function and of concomitant diseaseor other drug therapy in elderly patients.Non-Small Cell Lung Cancer

In a study conducted in chemotherapy-naive patients with NSCLC (TAX326), 148patients (36%) in the docetaxel+cisplatin group were 65 years of age or greater. Therewere 128 patients (32%) in the vinorelbine+cisplatin group 65 years of age or greater. Inthe docetaxel+cisplatin group, patients less than 65 years of age had a median survivalof 10.3 months (95% CI: 9.1 months, 11.8 months) and patients 65 years or older had

2

2 2 22 2

2 2

2

2

2

a median survival of 12.1 months (95% CI: 9.3 months, 14 months). In patients 65years of age or greater treated with docetaxel+cisplatin, diarrhea (55%), peripheraledema (39%) and stomatitis (28%) were observed more frequently than in thevinorelbine+cisplatin group (diarrhea 24%, peripheral edema 20%, stomatitis 20%).Patients treated with docetaxel+cisplatin who were 65 years of age or greater weremore likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) andstomatitis (28%) compared to patients less than the age of 65 administered the sametreatment (43%, 31%, 31% and 21%, respectively).When docetaxel was combined with carboplatin for the treatment of chemotherapy-naive, advanced non-small cell lung carcinoma, patients 65 years of age or greater(28%) experienced higher frequency of infection compared to similar patients treatedwith docetaxel+cisplatin, and a higher frequency of diarrhea, infection and peripheraledema than elderly patients treated with vinorelbine+cisplatin.Prostate Cancer

Of the 333 patients treated with docetaxel every three weeks plus prednisone in theprostate cancer study (TAX327), 209 patients were 65 years of age or greater and 68patients were older than 75 years. In patients treated with docetaxel every three weeks,the following treatment emergent adverse reactions occurred at rates ≥10% higher inpatients 65 years of age or greater compared to younger patients: anemia (71% vs.59%), infection (37% vs. 24%), nail changes (34% vs. 23%), anorexia (21% vs. 10%),weight loss (15% vs. 5%) respectively.Breast Cancer

In the adjuvant breast cancer trial (TAX316), docetaxel in combination with doxorubicinand cyclophosphamide was administered to 744 patients of whom 48 (6%) were 65years of age or greater. The number of elderly patients who received this regimen wasnot sufficient to determine whether there were differences in safety and efficacybetween elderly and younger patients.Gastric Cancer

Among the 221 patients treated with docetaxel injection in combination with cisplatin andfluorouracil in the gastric cancer study, 54 were 65 years of age or older and 2 patientswere older than 75 years. In this study, the number of patients who were 65 years ofage or older was insufficient to determine whether they respond differently fromyounger patients. However, the incidence of serious adverse reactions was higher in theelderly patients compared to younger patients. The incidence of the following adversereactions (all grades, regardless of relationship): lethargy, stomatitis, diarrhea, dizziness,edema, febrile neutropenia/neutropenic infection occurred at rates ≥10% higher inpatients who were 65 years of age or older compared to younger patients. Elderlypatients treated with TCF should be closely monitored.Head and Neck Cancer

Among the 174 and 251 patients who received the induction treatment with docetaxelinjection in combination with cisplatin and fluorouracil (TPF) for SCCHN in the TAX323and TAX324 studies, 18 (10%) and 32 (13%) of the patients were 65 years of age orolder, respectively.These clinical studies of docetaxel injection in combination with cisplatin and fluorouracilin patients with SCCHN did not include sufficient numbers of patients aged 65 and over

to determine whether they respond differently from younger patients. Other reportedclinical experience with this treatment regimen has not identified differences inresponses between elderly and younger patients.

8.6 Hepatic ImpairmentAvoid docetaxel in patients with bilirubin >ULN and patients with AST and/or ALT >1.5 xULN concomitant with alkaline phosphatase >2.5 x ULN [see Boxed Warning, Warningsand Precautions (5.2), Clinical Pharmacology (12.3)].

The alcohol content of Docetaxel Injection should be taken into account when given topatients with hepatic impairment [see Warnings and Precautions (5.13)].

10. OVERDOSAGEThere is no known antidote for Docetaxel Injection overdosage. In case of overdosage,the patient should be kept in a specialized unit where vital functions can be closelymonitored. Anticipated complications of overdosage include: bone marrow suppression,peripheral neurotoxicity, and mucositis. Patients should receive therapeutic G-CSF assoon as possible after discovery of overdose. Other appropriate symptomatic measuresshould be taken, as needed.In two reports of overdose, one patient received 150 mg/m and the other received 200mg/m as 1-hour infusions. Both patients experienced severe neutropenia, mildasthenia, cutaneous reactions, and mild paresthesia, and recovered without incident. Inmice, lethality was observed following single intravenous doses that were ≥154 mg/kg(about 4.5 times the human dose of 100 mg/m on a mg/m basis); neurotoxicityassociated with paralysis, non-extension of hind limbs, and myelin degeneration wasobserved in mice at 48 mg/kg (about 1.5 times the human dose of 100 mg/m basis). Inmale and female rats, lethality was observed at a dose of 20 mg/kg (comparable to thehuman dose of 100 mg/m on a mg/m basis) and was associated with abnormal mitosisand necrosis of multiple organs.

11. DESCRIPTIONDocetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared bysemisynthesis beginning with a precursor extracted from the renewable needle biomassof yew plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine,N-tert-butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate. Docetaxel has the following structural formula:

22

2 2

2

2 2

Docetaxel is a white to almost-white powder with an empirical formula of C H NO ,and a molecular weight of 807.88. It is highly lipophilic and practically insoluble in water.Docetaxel Injection is a clear, colorless to pale yellow solution. Docetaxel Injection issterile, non-pyrogenic, and is available in multiple-dose vials, supplied as 20 mg/2 mL, 80mg/8 mL and 160 mg/16 mL.Each mL of Docetaxel Injection contains 10 mg docetaxel, 275.9 mg alcohol 96% (v/v), 4mg citric acid, 648 mg polyethylene glycol 300, and 80 mg polysorbate 80.

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of ActionDocetaxel is an antineoplastic agent that acts by disrupting the microtubular network incells that is essential for mitotic and interphase cellular functions. Docetaxel binds to freetubulin and promotes the assembly of tubulin into stable microtubules whilesimultaneously inhibiting their disassembly. This leads to the production of microtubulebundles without normal function and to the stabilization of microtubules, which results inthe inhibition of mitosis in cells. Docetaxel's binding to microtubules does not alter thenumber of protofilaments in the bound microtubules, a feature which differs from mostspindle poisons currently in clinical use.

12.3 PharmacokineticsAbsorption: The pharmacokinetics of docetaxel has been evaluated in cancer patientsafter administration of 20 mg/m to 115 mg/m in phase 1 studies. The area under thecurve (AUC) was dose proportional following doses of 70 mg/m to 115 mg/m withinfusion times of 1 to 2 hours. Docetaxel's pharmacokinetic profile is consistent with athree-compartment pharmacokinetic model, with half-lives for the α, β, and γ phases of4 min, 36 min, and 11.1 hr, respectively. Mean total body clearance was 21 L/h/m .Distribution: The initial rapid decline represents distribution to the peripheralcompartments and the late (terminal) phase is due, in part, to a relatively slow efflux ofdocetaxel from the peripheral compartment. Mean steady state volume of distributionwas 113 L. In vitro studies showed that docetaxel is about 94% protein bound, mainly toα -acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the in vitrobinding to plasma proteins was found to be approximately 97%. Dexamethasone doesnot affect the protein binding of docetaxel.

43 53 14

2 22 2

2

1

Metabolism: In vitro drug interaction studies revealed that docetaxel is metabolized bythe CYP3A4 isoenzyme, and its metabolism may be modified by the concomitantadministration of compounds that induce, inhibit, or are metabolized by cytochromeP450 3A4 [see Drug Interactions (7)].

Elimination: A study of C-docetaxel was conducted in three cancer patients.Docetaxel was eliminated in both the urine and feces following oxidative metabolism ofthe tert-butyl ester group, but fecal excretion was the main elimination route. Within 7days, urinary and fecal excretion accounted for approximately 6% and 75% of theadministered radioactivity, respectively. About 80% of the radioactivity recovered infeces is excreted during the first 48 hours as 1 major and 3 minor metabolites with verysmall amounts (less than 8%) of unchanged drug.Specific PopulationsEffect of Age: A population pharmacokinetic analysis was carried out after docetaxeltreatment of 535 patients dosed at 100 mg/m . Pharmacokinetic parameters estimatedby this analysis were very close to those estimated from phase 1 studies. Thepharmacokinetics of docetaxel was not influenced by age.Effect of Gender: The population pharmacokinetics analysis described above alsoindicated that gender did not influence the pharmacokinetics of docetaxel.Hepatic Impairment:The population pharmacokinetic analysis described above indicatedthat in patients with clinical chemistry data suggestive of mild to moderate liverimpairment (AST and/or ALT >1.5 times ULN concomitant with alkaline phosphatase>2.5 times ULN), total body clearance was lowered by an average of 27%, resulting in a38% increase in systemic exposure (AUC). This average, however, includes a substantialrange and there is, at present, no measurement that would allow recommendation fordose adjustment in such patients. Patients with combined abnormalities of transaminaseand alkaline phosphatase should not be treated with Docetaxel Injection. Patients withsevere hepatic impairment have not been studied [see Warnings and Precautions (5.2),Use in Specific Populations (8.6)].

Effect of Race:Mean total body clearance for Japanese patients dosed at the range of 10mg/m to 90 mg/m was similar to that of European/American populations dosed at 100mg/m , suggesting no significant difference in the elimination of docetaxel in the twopopulations.Drug Interaction StudiesEffect of Ketoconazole: The effect of ketoconazole (a strong CYP3A4 inhibitor) on thepharmacokinetics of docetaxel was investigated in 7 cancer patients. Patients wererandomized to receive either docetaxel (100 mg/m intravenous) alone or docetaxel (10mg/m intravenous) in combination with ketoconazole (200 mg orally once daily for 3days) in a crossover design with a 3-week washout period. The results of this studyindicated that the mean dose-normalized AUC of docetaxel was increased 2.2-fold andits clearance was reduced by 49% when docetaxel was co-administered withketoconazole [see Dosage and Administration (2.7), Drug Interactions (7)].

Effect of Combination Therapies:

•

14

2

2 22

22

Dexamethasone: Docetaxel total body clearance was not modified by pretreatmentwith dexamethasone.

•

•

•

•

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenicity studies with docetaxel have not been performed.Docetaxel was clastogenic in the in vitro chromosome aberration test in CHO-K cellsand in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg(about 1/60 to 1/15 the recommended human dose on a mg/m basis). Docetaxelwas not mutagenic in the Ames test or the CHO/HGPRT gene mutation assays.Docetaxel did not reduce fertility in rats when administered in multiple intravenous dosesof up to 0.3 mg/kg (about 1/50 the recommended human dose on a mg/m basis), butdecreased testicular weights were reported. This correlates with findings of a 10-cycletoxicity study (dosing once every 21 days for 6 months) in rats and dogs in whichtesticular atrophy or degeneration was observed at intravenous doses of 5 mg/kg inrats and 0.375 mg/kg in dogs (about 1/3 and 1/15 the recommended human doseon a mg/m basis, respectively). An increased frequency of dosing in rats producedsimilar effects at lower dose levels.

14. CLINICAL STUDIES

14.1 Locally Advanced or Metastatic Breast CancerThe efficacy and safety of docetaxel have been evaluated in locally advanced ormetastatic breast cancer after failure of previous chemotherapy (alkylating agent-containing regimens or anthracycline-containing regimens).Randomized Trials

Cisplatin: Clearance of docetaxel in combination therapy with cisplatin was similar tothat previously observed following monotherapy with docetaxel. Thepharmacokinetic profile of cisplatin in combination therapy with docetaxel wassimilar to that observed with cisplatin alone.Cisplatin and Fluorouracil: The combined administration of docetaxel, cisplatin andfluorouracil in 12 patients with solid tumors had no influence on thepharmacokinetics of each individual drug.Prednisone: A population pharmacokinetic analysis of plasma data from 40 patientswith metastatic castration-resistant prostate cancer indicated that docetaxelsystemic clearance in combination with prednisone is similar to that observedfollowing administration of docetaxel alone.Cyclophosphamide and Doxorubicin: A study was conducted in 30 patients withadvanced breast cancer to determine the potential for drug-drug-interactionsbetween docetaxel (75 mg/m ), doxorubicin (50 mg/m ), and cyclophosphamide(500 mg/m ) when administered in combination. The co-administration of docetaxelhad no effect on the pharmacokinetics of doxorubicin and cyclophosphamide whenthe three drugs were given in combination compared to co-administration ofdoxorubicin and cyclophosphamide only. In addition, doxorubicin andcyclophosphamide had no effect on docetaxel plasma clearance when the threedrugs were given in combination compared to historical data for docetaxelmonotherapy.

2 22

1

th th 2

th 2

rd th2

In one randomized trial, patients with a history of prior treatment with an anthracycline-containing regimen were assigned to treatment with docetaxel (100 mg/m every 3weeks) or the combination of mitomycin (12 mg/m every 6 weeks) and vinblastine (6mg/m every 3 weeks). Two hundred three patients were randomized to docetaxel and189 to the comparator arm. Most patients had received prior chemotherapy formetastatic disease; only 27 patients on the docetaxel arm and 33 patients on thecomparator arm entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint wastime to progression. The following table summarizes the study results (see Table 12).Table 12 - Efficacy of Docetaxel in the Treatment of Breast Cancer PatientsPreviously Treated with an Anthracycline-Containing Regimen (Intent-to-Treat Analysis)

*

EfficacyParameter

Docetaxel(n=203)

Mitomycin/Vinblastine

(n=189)

p-value

MedianSurvival

11.4months

8.7 months

p=0.01Log Rank

Risk Ratio ,Mortality(Docetaxel:Control)

0.73

95% CI(Risk Ratio)

0.58-0.93

MedianTime toProgression

4.3months

2.5 months

Risk Ratio ,Progression(Docetaxel:Control)

0.75 p=0.01Log Rank

95% CI(Risk Ratio)

0.61-0.94

OverallResponseRate

28.1% 9.5% p<0.0001Chi

SquareCompleteResponseRate

3.4% 1.6%

In a second randomized trial, patients previously treated with an alkylating-containingregimen were assigned to treatment with docetaxel (100 mg/m ) or doxorubicin (75mg/m ) every 3 weeks. One hundred sixty-one patients were randomized to docetaxeland 165 patients to doxorubicin. Approximately one-half of patients had received priorchemotherapy for metastatic disease, and one-half entered the study following relapse

22

2

For the risk ratio, a value less than 1.00 favorsdocetaxel.

*

*

22

after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases.The primary endpoint was time to progression. The study results are summarized below(see Table 13).Table 13 - Efficacy of Docetaxel in the Treatment of Breast Cancer PatientsPreviously Treated with an Alkylating-Containing Regimen (Intent-to-TreatAnalysis)

*

EfficacyParameter

Docetaxel(n=161)

Doxorubicin(n=165)

p-value

MedianSurvival

14.7months

14.3 months

p=0.39LogRank

Risk Ratio ,Mortality(Docetaxel:Control)95% CI(Risk Ratio)

0.89

0.68-1.16MedianTime toProgression

6.5months

5.3 months

p=0.45LogRank

Risk Ratio ,Progression(Docetaxel:Control)95% CI(Risk Ratio)

0.93

0.71-1.16OverallResponseRateCompleteResponseRate

45.3%

6.8%

29.7%

4.2%

p=0.004Chi

Square

In another multicenter open-label, randomized trial (TAX313), in the treatment ofpatients with advanced breast cancer who progressed or relapsed after one priorchemotherapy regimen, 527 patients were randomized to receive docetaxelmonotherapy 60 mg/m (n=151), 75 mg/m (n=188) or 100 mg/m (n=188). In thistrial, 94% of patients had metastatic disease and 79% had received prior anthracyclinetherapy. Response rate was the primary endpoint. Response rates increased withdocetaxel dose: 19.9% for the 60 mg/m group compared to 22.3% for the 75 mg/mand 29.8% for the 100 mg/m group; pair-wise comparison between the 60 mg/m and100 mg/m groups was statistically significant (p=0.037).Single Arm StudiesDocetaxel at a dose of 100 mg/m was studied in six single arm studies involving a totalof 309 patients with metastatic breast cancer in whom previous chemotherapy had

For the risk ratio, a value less than 1.00 favorsdocetaxel.

*

*

2 2 2

2 22 2

2

2

failed. Among these, 190 patients had anthracycline-resistant breast cancer, defined asprogression during an anthracycline-containing chemotherapy regimen for metastaticdisease, or relapse during an anthracycline-containing adjuvant regimen. Inanthracycline-resistant patients, the overall response rate was 37.9% (72/190; 95% C.I.:31.0-44.8) and the complete response rate was 2.1%.Docetaxel was also studied in three single arm Japanese studies at a dose of 60 mg/m ,in 174 patients who had received prior chemotherapy for locally advanced or metastaticbreast cancer. Among 26 patients whose best response to an anthracycline had beenprogression, the response rate was 34.6% (95% C.I.: 17.2-55.7), similar to the responserate in single arm studies of 100 mg/m .

14.2 Adjuvant Treatment of Breast CancerA multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety ofdocetaxel for the adjuvant treatment of patients with axillary-node-positive breastcancer and no evidence of distant metastatic disease. After stratification according tothe number of positive lymph nodes (1-3, 4+), 1491 patients were randomized toreceive either docetaxel 75 mg/m administered 1-hour after doxorubicin 50 mg/m andcyclophosphamide 500 mg/m (TAC arm), or doxorubicin 50 mg/m followed byfluorouracil 500 mg/m and cyclophosphamide 500 mg/m (FAC arm). Both regimenswere administered every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hourinfusion; all other drugs were given as intravenous bolus on day 1. In both arms, afterthe last cycle of chemotherapy, patients with positive estrogen and/or progesteronereceptors received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapywas prescribed according to guidelines in place at participating institutions and wasgiven to 69% of patients who received TAC and 72% of patients who received FAC.Results from a second interim analysis (median follow-up 55 months) are as follows: Instudy TAX316, the docetaxel-containing combination regimen TAC showed significantlylonger disease-free survival (DFS) than FAC (hazard ratio=0.74; 2-sided 95% CI=0.60,0.92, stratified log rank p=0.0047). The primary endpoint, disease-free survival, includedlocal and distant recurrences, contralateral breast cancer and deaths from any cause.The overall reduction in risk of relapse was 25.7% for TAC-treated patients (see Figure1).At the time of this interim analysis, based on 219 deaths, overall survival was longer forTAC than FAC (hazard ratio=0.69, 2-sided 95% CI=0.53, 0.90) (see Figure 2). There willbe further analysis at the time survival data mature.Figure 1 - TAX316 Disease Free Survival K-M Curve

2

2

2 22 2

2 2

Figure 2 - TAX316 Overall Survival K-M Curve

The following table describes the results of subgroup analyses for DFS and OS (seeTable 14).Table 14 - Subset Analyses-Adjuvant Breast Cancer Study

DiseaseFree

Survival

OverallSurvival

Patientsubset

Numberof

patients

Hazardratio

95%CI

Hazardratio*

95%CI

No. ofpositivenodesOverall 744 0.74 (0.60,

0.92)0.69 (0.53,

0.90)1-3 467 0.64 (0.47,

0.87)0.45 (0.29,

0.70)4+ 277 0.84 (0.63,

1.12)0.93 (0.66,

1.32)Receptor

*

*

statusPositive 566 0.76 (0.59,

0.98)0.69 (0.48,

0.99)Negative 178 0.68 (0.48,

0.97)0.66 (0.44,

0.98)

14.3 Non-Small Cell Lung Cancer (NSCLC)The efficacy and safety of docetaxel has been evaluated in patients with unresectable,locally advanced or metastatic non-small cell lung cancer whose disease has failed priorplatinum-based chemotherapy or in patients who are chemotherapy-naive.Monotherapy with Docetaxel for NSCLC Previously Treated with Platinum-Based ChemotherapyTwo randomized, controlled trials established that a docetaxel dose of 75 mg/m wastolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy (see below). Docetaxel at a dose of 100 mg/m , however, wasassociated with unacceptable hematologic toxicity, infections, and treatment-relatedmortality and this dose should not be used [see Boxed Warning, Dosage andAdministration (2.7), Warnings and Precautions (5.3)].

One trial (TAX317), randomized patients with locally advanced or metastatic non-smallcell lung cancer, a history of prior platinum-based chemotherapy, no history of taxaneexposure, and an ECOG performance status ≤2 to docetaxel or best supportive care.The primary endpoint of the study was survival. Patients were initially randomized todocetaxel 100 mg/m or best supportive care, but early toxic deaths at this dose led toa dose reduction to docetaxel 75 mg/m . A total of 104 patients were randomized in thisamended study to either docetaxel 75 mg/m or best supportive care.In a second randomized trial (TAX320), 373 patients with locally advanced or metastaticnon-small cell lung cancer, a history of prior platinum-based chemotherapy, and anECOG performance status ≤2 were randomized to docetaxel 75 mg/m , docetaxel 100mg/m and a treatment in which the investigator chose either vinorelbine 30 mg/m days1, 8, and 15 repeated every 3 weeks or ifosfamide 2 g/m days 1-3 repeated every 3weeks. Forty percent of the patients in this study had a history of prior paclitaxelexposure. The primary endpoint was survival in both trials. The efficacy data for thedocetaxel 75 mg/m arm and the comparator arms are summarized in Table 15 andFigures 3 and 4 showing the survival curves for the two studies.Table 15 - Efficacy of Docetaxel in the Treatment of Non-Small Cell LungCancer Patients Previously Treated with a Platinum-Based ChemotherapyRegimen (Intent-to-Treat Analysis)

TAX317 TAX320Docetaxel Best DocetaxelControl75 mg/m

n=55Supportive

Caren=49

75 mg/mn=125

(V/I )n=123

A hazard ratio of less than 1 indicates that TAC isassociated with a longer disease-free survival oroverall survival compared to FAC.

2

2

22

2

22 2

2

2

2 2 *

*†‡§

OverallSurvivalLog-rankTest

p=0.01 p=0.13

Risk Ratio ,Mortality(Docetaxel:Control)

0.56 0.82

95% CI(Risk Ratio)

(0.35, 0.88) (0.63, 1.06)

MedianSurvival

7.5months

4.6 months 5.7months

5.6months

95% CI (5.5, 12.8) (3.7, 6.1) (5.1, 7.1) (4.4,7.9)

% 1-yearSurvival 37% 12% 30% 20%95% CI (24, 50) (2, 23) (22, 39) (13, 27)Time toProgression

12.3weeks 7.0 weeks 8.3 weeks 7.6

weeks95% CI (9.0, 18.3) (6.0, 9.3) (7.0, 11.7) (6.7,

10.1)ResponseRate 5.5% Not

Applicable5.7% 0.8%

95% CI (1.1, 15.1) (2.3, 11.3) (0.0,4.5)

Only one of the two trials (TAX317) showed a clear effect on survival, the primaryendpoint; that trial also showed an increased rate of survival to one year. In the secondstudy (TAX320) the rate of survival at one year favored docetaxel 75 mg/m .Figure 3 - TAX317 Survival K-M Curves - Docetaxel 75 mg/m versus BestSupportive Care

Vinorelbine/Ifosfamidea value less than 1.00 favors docetaxelp≤0.05uncorrected for multiple comparisons

†

‡

‡§ ‡§

‡

2

2

Figure 4 - TAX320 Survival K-M Curves - Docetaxel 75 mg/m versusVinorelbine or Ifosfamide Control

2

Patients treated with docetaxel at a dose of 75 mg/m experienced no deterioration inperformance status and body weight relative to the comparator arms used in thesetrials.Combination Therapy with Docetaxel for Chemotherapy-Naive NSCLCIn a randomized controlled trial (TAX326), 1218 patients with unresectable stage IIIB orIV NSCLC and no prior chemotherapy were randomized to receive one of threetreatments: docetaxel 75 mg/m as a 1-hour infusion immediately followed by cisplatin75 mg/m over 30 to 60 minutes every 3 weeks; vinorelbine 25 mg/m administeredover 6 to 10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m administeredon day 1 of cycles repeated every 4-weeks; or a combination of docetaxel andcarboplatin.The primary efficacy endpoint was overall survival. Treatment with docetaxel+cisplatindid not result in a statistically significantly superior survival compared tovinorelbine+cisplatin (see table below). The 95% confidence interval of the hazard ratio(adjusted for interim analysis and multiple comparisons) shows that the addition ofdocetaxel to cisplatin results in an outcome ranging from a 6% inferior to a 26%superior survival compared to the addition of vinorelbine to cisplatin. The results of afurther statistical analysis showed that at least (the lower bound of the 95% confidenceinterval) 62% of the known survival effect of vinorelbine when added to cisplatin (about a2-month increase in median survival; Wozniak et al. JCO, 1998) was maintained. The

2

22 2

2

efficacy data for the docetaxel+cisplatin arm and the comparator arm are summarizedin Table 16.Table 16 - Survival Analysis of Docetaxel in Combination Therapy forChemotherapy-Naive NSCLC

*

†

‡

ComparisonDocetaxel+Cisplatinn=408

Vinorelbine+Cisplatinn=405

Kaplan-MeierEstimate ofMedianSurvival

10.9 months 10 months

p-value 0.122EstimatedHazardRatio

0.88

Adjusted95% CI

(0.74, 1.06)

The second comparison in the same three-arm study, vinorelbine+cisplatin versusdocetaxel+carboplatin, did not demonstrate superior survival associated with thedocetaxel arm (Kaplan-Meier estimate of median survival was 9.1 months fordocetaxel+carboplatin compared to 10.0 months on the vinorelbine+cisplatin arm) andthe docetaxel+carboplatin arm did not demonstrate preservation of at least 50% of thesurvival effect of vinorelbine added to cisplatin. Secondary endpoints evaluated in thetrial included objective response and time to progression. There was no statisticallysignificant difference between docetaxel+cisplatin and vinorelbine+cisplatin with respectto objective response and time to progression (see Table 17).Table 17 - Response and TTP Analysis of Docetaxel in Combination Therapyfor Chemotherapy-Naive NSCLC

*†

Endpoint Docetaxel+Cisplatin

Vinorelbine+Cisplatin p-value

ObjectiveResponseRate(95% CI)

31.6%(26.5%,36.8%)

24.4%(19.8%, 29.2%)

NotSignificant

Median TimetoProgression(95% CI)

21.4weeks(19.3,24.6)

22.1 weeks(18.1, 25.6)

NotSignificant

From the superiority test (stratified log rank) comparingdocetaxel+cisplatin to vinorelbine+cisplatinHazard ratio of docetaxel+cisplatin versus vinorelbine+cisplatin. Ahazard ratio of less than 1 indicates that docetaxel+cisplatin isassociated with a longer survival.Adjusted for interim analysis and multiple comparisons.

*

†

‡

Adjusted for multiple comparisons.Kaplan-Meier estimates.

*

†*

14.4 Castration-Resistant Prostate CancerThe safety and efficacy of docetaxel in combination with prednisone in patients withmetastatic castration-resistant prostate cancer were evaluated in a randomizedmulticenter active control trial. A total of 1006 patients with Karnofsky PerformanceStatus (KPS) ≥60 were randomized to the following treatment groups:

••

•

All 3 regimens were administered in combination with prednisone 5 mg twice daily,continuously.In the docetaxel every three-week arm, a statistically significant overall survivaladvantage was demonstrated compared to mitoxantrone. In the docetaxel weekly arm,no overall survival advantage was demonstrated compared to the mitoxantrone controlarm. Efficacy results for the docetaxel every 3-week arm versus the control arm aresummarized in Table 18 and Figure 5.Table 18 - Efficacy of Docetaxel in the Treatment of Patients with MetastaticCastration-Resistant Prostate Cancer (Intent-to-Treat Analysis)

*

Docetaxel +Prednisone

Mitoxantrone+Prednisone

every 3weeks

every 3 weeks

Number ofpatients

335 337

Mediansurvival(months)

18.9 16.5

95% CI (17.0-21.2) (14.4-18.6)Hazardratio

0.761 -

95% CI (0.619-0.936) -p-value 0.0094 -

Figure 5 - TAX327 Survival K-M Curves

Docetaxel 75 mg/m every 3 weeks for 10 cycles.2Docetaxel 30 mg/m administered weekly for the first 5 weeks in a 6-week cycle for5 cycles.

2

Mitoxantrone 12 mg/m every 3 weeks for 10 cycles.2

Stratified log rank test. Threshold for statisticalsignificance = 0.0175 because of 3 arms.

*

14.5 Gastric AdenocarcinomaA multicenter, open-label, randomized trial was conducted to evaluate the safety andefficacy of docetaxel injection for the treatment of patients with advanced gastricadenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who hadnot received prior chemotherapy for advanced disease. A total of 445 patients with KPS>70 were treated with either docetaxel injection (T) (75 mg/m on day 1) in combinationwith cisplatin (C) (75 mg/m on day 1) and fluorouracil (F) (750 mg/m per day for 5days) or cisplatin (100 mg/m on day 1) and fluorouracil (1000 mg/m per day for 5days). The length of a treatment cycle was 3 weeks for the TCF arm and 4 weeks for theCF arm. The demographic characteristics were balanced between the two treatmentarms. The median age was 55 years, 71% were male, 71% were Caucasian, 24% were65 years of age or older, 19% had a prior curative surgery and 12% had palliativesurgery. The median number of cycles administered per patient was 6 (with a range of 1to 16) for the TCF arm compared to 4 (with a range of 1 to 12) for the CF arm. Time toprogression (TTP) was the primary endpoint and was defined as time fromrandomization to disease progression or death from any cause within 12 weeks of thelast evaluable tumor assessment or within 12 weeks of the first infusion of study drugsfor patients with no evaluable tumor assessment after randomization. The hazard ratio(HR) for TTP was 1.47 (CF/TCF, 95% CI: 1.19 to 1.83) with a significantly longer TTP(p=0.0004) in the TCF arm. Approximately 75% of patients had died at the time of thisanalysis. Overall survival was significantly longer (p=0.0201) in the TCF arm with a HR of

22 2

2 2

1.29 (95% CI: 1.04 to 1.61). Efficacy results are summarized in Table 19 and Figures 6and 7.Table 19 - Efficacy of Docetaxel Injection in the Treatment of Patients withGastric Adenocarcinoma

*

†

Endpoint TCFn=221

CFn=224

Median TTP(months)(95% CI)Hazard ratio(95% CI)p-value

5.6(4.86-5.91)

3.7(3.45-4.47)

0.68(0.55-0.84)

0.0004Median survival(months)(95% CI)Hazard ratio(95% CI)p-value

9.2(8.38-10.58)

8.6(7.16-9.46)

0.77(0.62-0.96)

0.0201OverallResponse Rate(CR+PR) (%)p-value

36.7 25.40.0106

Subgroup analyses were consistent with the overall results across age, gender andrace.Figure 6 - Gastric Cancer Study (TAX325) Time to Progression K-M Curve

For the hazard ratio (TCF/CF), valuesless than 1.00 favor the docetaxelinjection arm.Unstratified log-rank test.

*

†

*

†

Figure 7 - Gastric Cancer Study (TAX325) Survival K-M Curve

14.6 Head and Neck CancerInduction Chemotherapy Followed by Radiotherapy (TAX323)The safety and efficacy of docetaxel injection in the induction treatment of patients withsquamous cell carcinoma of the head and neck (SCCHN) was evaluated in a multicenter,open-label, randomized trial (TAX323). In this study, 358 patients with inoperable locallyadvanced SCCHN, and WHO performance status 0 or 1, were randomized to one of twotreatment arms. Patients on the docetaxel injection arm received docetaxel injection (T)75 mg/m followed by cisplatin (P) 75 mg/m on Day 1, followed by fluorouracil (F) 750mg/m per day as a continuous infusion on Days 1 to 5. The cycles were repeated everythree weeks for 4 cycles. Patients whose disease did not progress received radiotherapy(RT) according to institutional guidelines (TPF/RT). Patients on the comparator armreceived cisplatin (P) 100 mg/m on Day 1, followed by fluorouracil (F) 1000 mg/m /dayas a continuous infusion on Days 1 to 5. The cycles were repeated every three weeksfor 4 cycles. Patients whose disease did not progress received RT according toinstitutional guidelines (PF/RT). At the end of chemotherapy, with a minimal interval of 4weeks and a maximal interval of 7 weeks, patients whose disease did not progressreceived radiotherapy (RT) according to institutional guidelines. Locoregional therapywith radiation was delivered either with a conventional fraction regimen (1.8 Gy to 2 Gyonce a day, 5 days per week for a total dose of 66 to 70 Gy) or with anaccelerated/hyperfractionated regimen (twice a day, with a minimum interfraction

2 22

2 2

interval of 6 hours, 5 days per week, for a total dose of 70 to 74 Gy, respectively).Surgical resection was allowed following chemotherapy, before or after radiotherapy.The primary endpoint in this study, progression-free survival (PFS), was significantlylonger in the TPF arm compared to the PF arm, p=0.0077 (median PFS: 11.4 vs. 8.3months respectively) with an overall median follow up time of 33.7 months. Medianoverall survival with a median follow-up of 51.2 months was also significantly longer infavor of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.2 monthsrespectively).Efficacy results are presented in Table 20 and Figures 8 and 9.Table 20 - Efficacy of Docetaxel Injection in the Induction Treatment ofPatients with Inoperable Locally Advanced SCCHN (Intent-to-Treat Analysis)

Endpoint DocetaxelInjection +Cisplatin+

Fluorouraciln=177

Cisplatin+Fluorouracil

n=181

Medianprogressionfree survival(months)

11.4 8.3

(95% CI) (10.1-14.0) (7.4-9.1)AdjustedHazard ratio(95% CI)p-value

0.71(0.56-0.91)

0.0077

Median survival(months) (95%CI)

18.6(15.7-24.0)

14.2(11.5-18.7)

Hazard ratio(95% CI)p-value

0.71(0.56-0.90)

0.0055Best overallresponse (CR+ PR) tochemotherapy(%)(95% CI)

67.8(60.4-74.6)

53.6(46.0-61.0)

p-value 0.006Best overallresponse (CR+ PR) to studytreatment[chemotherapy+/-radiotherapy](%)

72.3 58.6

*

†

‡

*

†

‡

(95% CI) (65.1-78.8) (51.0-65.8)p-value 0.006

A Hazard ratio of less than 1 favorsdocetaxel injection+cisplatin+fluorouracil

Figure 8 - TAX323 Progression-Free Survival K-M Curve

Figure 9 - TAX323 Overall Survival K-M Curve

Stratified log-rank test based on primarytumor site.Stratified log-rank test, not adjusted formultiple comparisons.Chi square test, not adjusted for multiplecomparisons.

‡

Induction Chemotherapy Followed by Chemoradiotherapy (TAX324)The safety and efficacy of docetaxel injection in the induction treatment of patients withlocally advanced (unresectable, low surgical cure, or organ preservation) SCCHN wasevaluated in a randomized, multicenter open-label trial (TAX324). In this study, 501patients, with locally advanced SCCHN, and a WHO performance status of 0 or 1, wererandomized to one of two treatment arms. Patients on the docetaxel injection armreceived docetaxel injection (T) 75 mg/m by intravenous infusion on day 1 followed bycisplatin (P) 100 mg/m administered as a 30-minute to three-hour intravenous infusion,followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m /day fromday 1 to day 4. The cycles were repeated every 3 weeks for 3 cycles. Patients on thecomparator arm received cisplatin (P) 100 mg/m as a 30-minute to three-hourintravenous infusion on day 1 followed by the continuous intravenous infusion offluorouracil (F) 1000 mg/m /day from day 1 to day 5. The cycles were repeated every 3weeks for 3 cycles.All patients in both treatment arms who did not have progressive disease were toreceive 7 weeks of chemoradiotherapy (CRT) following induction chemotherapy 3 to 8weeks after the start of the last cycle. During radiotherapy, carboplatin (AUC 1.5) wasgiven weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiationwas delivered with megavoltage equipment using once daily fractionation (2 Gy per day,5 days per week for 7 weeks for a total dose of 70-72 Gy). Surgery on the primary siteof disease and/or neck could be considered at anytime following completion of CRT. Theprimary efficacy endpoint, overall survival (OS), was significantly longer (log-rank test,p=0.0058) with the docetaxel injection-containing regimen compared to PF (median OS:70.6 vs 30.1 months respectively, hazard ratio [HR]=0.70, 95% confidence interval[CI]=0.54 to 0.90). Overall survival results are presented in Table 21 and Figure 10.Table 21 - Efficacy of Docetaxel Injection in the Induction Treatment ofPatients with Locally Advanced SCCHN (Intent-to-Treat Analysis)

Endpoint Docetaxel Cisplatin+

22

2

2

2

*

Injection +Cisplatin+

Fluorouraciln=255

Fluorouraciln=246

Medianoverallsurvival(months)(95% CI)

70.6(49.0-NE)

30.1(20.9-51.5)

Hazard ratio:(95% CI)p-value

0.70(0.54-0.90)

0.0058A Hazard ratio of less than 1 favorsdocetaxelinjection+cisplatin+fluorouracil.NE - not estimable.

Figure 10 - TAX324 Overall Survival K-M Curve

15. REFERENCES

un-adjusted log-rank test.

*

1.

16. HOW SUPPLIED/STORAGE AND HANDLING

16.1 How SuppliedDocetaxel Injection is supplied in a multiple-dose vial as a sterile, pyrogen-free solution.Docetaxel Injection requires NO prior dilution with a diluent and is ready to add to theinfusion solution. The following strengths are available:

Strength NDCNumber

Volume

20 mg/2mL

66758-050-01

Carton of one 2 mLMultiple-Dose Vial

80 mg/8mL

66758-050-02

Carton of one 8 mLMultiple-Dose Vial

160 mg/16mL

66758-050-03

Carton of one 16 mLMultiple-Dose Vial

16.2 StorageStore between 2°C and 25°C (36°F and 77°F). Retain in the original package to protectfrom bright light. Freezing does not adversely affect the product.After initial puncture, Docetaxel Injection multiple-dose vials are stable for 28 days whenstored between 2ºC to 8ºC and at room temperature, with or without protection fromlight.

16.3 Handling and DisposalDocetaxel Injection is a cytotoxic drug. Follow applicable special handling and disposalprocedures.

17. PATIENT COUNSELING INFORMATIONAdvise the patient to read the FDA-approved patient labeling (Patient Information).Bone Marrow SuppressionAdvise patients that periodic assessment of their blood count will be performed todetect neutropenia, thrombocytopenia, and/ or anemia [see Contraindications (4),Warnings and Precautions (5.3)]. Instruct patients to monitor their temperaturefrequently and immediately report any occurrence of fever.Enterocolitis and Neutropenic ColitisAdvise patients of the symptoms of colitis, such as abdominal pain or tenderness,and/or diarrhea, with or without fever, and instruct patients to promptly contact theirhealthcare provider if they experience these symptoms [see Dosage and Administration(2.7) and Warnings and Precautions (5.4)].Hypersensitivity Reactions

“OSHA Hazardous Drugs.” http://www.osha.gov/SLTC/hazardousdrugs/index.html

1

Ask patients whether they have previously received paclitaxel therapy, and if they haveexperienced a hypersensitivity reaction to paclitaxel. Instruct patients to immediatelyreport to their healthcare provider signs of a hypersensitivity reaction [seeContraindications (4), Warnings and Precautions (5.5)].Fluid RetentionAdvise patients to report signs of fluid retention such as peripheral edema in the lowerextremities, weight gain, and dyspnea immediately to their healthcare provider [seeWarnings and Precautions (5.6)].Second Primary MalignanciesAdvise patients on the risk of second primary malignancies during treatment withdocetaxel [see Warnings and Precautions (5.7)].Cutaneous ReactionsAdvise patients that localized erythema of the extremities and severe skin toxicities mayoccur. Instruct patients to immediately report severe cutaneous reactions to theirhealthcare provider [see Dosage and Administration (2.7) and Warnings and Precautions(5.8)].Neurologic ReactionsAdvise patients that neurosensory symptoms or peripheral neuropathy may occur.Instruct patients to immediately report neurologic reactions to their healthcare provider[see Dosage and Administration (2.7) and Warnings and Precautions (5.9)].Eye DisordersAdvise patients that vision disturbances and excessive tearing are associated withDocetaxel Injection administration. Instruct patients to immediately report any visionchanges to their healthcare provider [see Warnings and Precautions (5.10)].Gastrointestinal ReactionsExplain to patients that nausea, vomiting, diarrhea, and constipation are associated withDocetaxel Injection administration. Instruct patients to report any severe events to theirhealthcare provider [see Adverse Reactions (6)].Cardiac DisordersAdvise patients to report any irregular and/or rapid heartbeat, severe shortness ofbreath, dizziness, and/or fainting immediately to their healthcare provider [see AdverseReactions (6)].Other Common Adverse ReactionsAdvise patients that other common adverse reactions associated with DocetaxelInjection may include alopecia (cases of permanent hair loss have been reported),asthenia, anorexia, dysgeusia, mucositis, myalgia, nail disorders, or pain. Instructpatients to report these reactions to their healthcare provider if serious events occur[see Adverse Reactions (6)].Importance of CorticosteroidsExplain the significance of oral corticosteroids such as dexamethasone administration to

the patient to help facilitate compliance. Instruct patients to report to their healthcareprovider if they were not compliant with the oral corticosteroid regimen [see Dosage andAdministration (2.6)].Embryo-Fetal ToxicityDocetaxel Injection can cause fetal harm. Advise patients to inform their healthcareprovider of a known or suspected pregnancy. Advise patients to avoid becomingpregnant while receiving this drug. Advise female patients of reproductive potential touse effective contraceptives during treatment and for 6 months after the last dose ofDocetaxel Injection. Advise male patients with female partners of reproductive potentialto use effective contraception during treatment and for 3 months after the last dose ofDocetaxel Injection [see Warnings and Precautions (5.12), and Use in SpecificPopulations (8.1, 8.3)].LactationAdvise women not to breastfeed during Docetaxel Injection treatment and for 1 weekafter the last dose [see Use in Specific Populations (8.2)].InfertilityAdvise males of reproductive potential that Docetaxel Injection may impair fertility [seeNonclinical Toxicology (13.1)].Alcohol Content in Docetaxel InjectionExplain to patients the possible effects of the alcohol content in Docetaxel Injection,including possible effects on the central nervous system [see Warnings and Precautions(5.13)].Tumor Lysis SyndromeAdvise patients of the potential risk of tumor lysis syndrome and to immediately reportany signs or symptoms associated with this event (nausea, vomiting, confusion,shortness of breath, seizure, irregular heartbeat, dark or cloudy urine, reduced amountof urine, unusual tiredness, muscle cramps) to their healthcare provider. Advise patientsof the importance of keeping scheduled appointment for blood work or other laboratorytests and of drinking adequate fluids to avoid dehydration [see Warnings andPrecautions (5.14)].

Ability to Drive or Operate MachinesExplain to patients that Docetaxel Injection may impair their ability to drive or operatemachines due to its side effects [see Adverse Reactions (6)] or due to the alcoholcontent of Docetaxel Injection [see Warnings and Precautions (5.13)]. Advise them notto drive or use machines if they experience these side effects during treatment.Drug InteractionsInform patients about the risk of drug interactions and the importance of providing a listof prescription and non-prescription drugs to their healthcare provider [see DrugInteractions (7)].Manufactured for:Sandoz Inc.

Princeton, NJ 08540Manufactured by:EBEWE Pharma Ges.m.b.H. Nfg.KGA-4866 Unterach, Austria

Patient InformationDocetaxel (doe-se-TAKS-el) Injectionfor intravenous use

What is the most important information I should know aboutDocetaxel Injection?Docetaxel Injection can cause serious side effects, includingdeath.

•

•

•

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The chance of death in people who receive DocetaxelInjection is higher if you:

ooo

have liver problemsreceive high doses of Docetaxel Injectionhave non-small cell lung cancer and have been treated withchemotherapy medicines that contain platinum

Docetaxel Injection can affect your blood cells. Yourhealthcare provider should do routine blood tests duringtreatment with Docetaxel Injection. This will include regularchecks of your white blood cell counts. If your white blood cellsare too low, your healthcare provider may not treat you withDocetaxel Injection until you have enough white blood cells.People with low white blood cell counts can develop life-threatening infections. The earliest sign of infection may be fever.Follow your healthcare provider's instructions for how often totake your temperature during treatment with Docetaxel Injection.Call your healthcare provider right away if you have a fever.Swelling (inflammation) of the small intestine and colon.This can happen at any time during treatment and could lead todeath as early as the first day you get symptoms. Tell yourhealthcare provider right away if you develop new or worsesymptoms of intestinal problems, including stomach (abdominal)pain or tenderness or diarrhea, with or without fever.Severe allergic reactions are medical emergencies that canhappen in people who receive Docetaxel Injection and can lead todeath. You may be at higher risk of developing a severe allergicreaction to Docetaxel Injection if you are allergic to paclitaxel.Your healthcare provider will monitor you closely for allergicreactions during your Docetaxel Injection infusion.Tell your healthcare provider right away if you have any of thesesigns of a severe allergic reaction:

•

•

•

oo

o

What is Docetaxel Injection?Docetaxel Injection is a prescription anticancer medicine used to treatcertain people with:

•••••

signs of a severe allergic reaction:

oo

o

trouble breathingsudden swelling of your face, lips, tongue, throat, or troubleswallowinghives (raised bumps), rash, or redness all over your body

Your body may hold too much fluid (severe fluidretention) during treatment with Docetaxel Injection. This canbe life threatening. To decrease the chance of this happening,you must take another medicine, a corticosteroid, before eachDocetaxel Injection treatment. You must take the corticosteroidexactly as your healthcare provider tells you. Tell your healthcareprovider or nurse before your Docetaxel Injection treatment ifyou forgot to take your corticosteroid dose or do not take it asyour healthcare provider tells you. Tell your healthcare providerright away if you have swelling in your legs or feet, weight gain orshortness of breath.Risk of new cancers. An increase in new (second) cancershas happened in people treated with Docetaxel Injection togetherwith certain other anticancer treatments. This includes certainblood cancers, such as acute myeloid leukemia (AML),myelodysplastic syndrome (MDS), non-Hodgkin’s Lymphoma(NHL), and kidney cancer.

o Changes in blood counts due to leukemia and other blooddisorders may occur years after treatment with DocetaxelInjection.

Your healthcare provider will check you for new cancers duringand after your treatment with Docetaxel Injection.Severe skin problems.Tell your healthcare provider right away if you have any of thesesigns of a severe skin reaction:redness and swelling of your arms and legs.blistering, peeling or bleeding on any part of your skin (includingyour lips, eyes, mouth, nose, genitals, hands or feet) with orwithout a rash. You may also have flu-like symptoms such asfever, chills, or muscle aches.red, scaly rash all over your body with blisters small red or whitebumps under the skin that contain pus (pustules) and fever.

breast cancernon-small cell lung cancerprostate cancerstomach cancerhead and neck cancer

It is not known if Docetaxel Injection is effective in children.Do not receive Docetaxel Injection if you:

••

See "What is the most important information I should knowabout Docetaxel Injection?" for the signs and symptoms of asevere allergic reaction.See the end of this Patient Information for a complete list of theingredients in Docetaxel Injection.Before you receive Docetaxel Injection, tell your healthcareprovider about all of your medical conditions, including if you:

•

•••

o

o

•

Tell your healthcare provider about all the medicines youtake, including prescription and over-the-counter medicines,vitamins, and herbal supplements. Docetaxel Injection may affect theway other medicines work, and other medicines may affect the wayDocetaxel Injection works. Know the medicines you take. Keep a list of

have a low white blood cell counthave had a severe allergic reaction to:

o docetaxel, the active ingredient in Docetaxel Injection,

or

o any other medicines that contain polysorbate 80. Ask yourhealthcare provider or pharmacist if you are not sure.

are allergic to any medicines, including paclitaxel. See "Do notreceive Docetaxel Injection if you".have liver problemshave kidney problemsare pregnant or plan to become pregnant. Docetaxel Injectioncan harm your unborn baby. You should not become pregnantduring treatment with Docetaxel Injection. Tell your healthcareprovider if you become pregnant or you think you may bepregnant during treatment with Docetaxel Injection.Females who are able to become pregnant:Your healthcare provider will check to see if you are pregnantbefore you start treatment with Docetaxel Injection.You should use effective birth control (contraception) duringtreatment with Docetaxel Injection and for 6 months after thelast dose.Males with female partners who are able to become pregnantshould use effective birth control during treatment withDocetaxel Injection and for 3 months after the last dose.Talk to your healthcare provider if you have questions about birthcontrol options that are right for you.are breastfeeding or plan to breastfeed. It is not known ifDocetaxel Injection passes into your breast milk. Do notbreastfeed during treatment with Docetaxel Injection and for 1week after the last dose.

them to show your healthcare provider and pharmacist when you geta new medicine.How will I receive Docetaxel Injection?

•

••

•

•

What are the possible side effects of Docetaxel Injection?Docetaxel Injection may cause serious side effects includingdeath.

•

•

•

•

•

oooo

Docetaxel Injection will be given to you as an intravenous (IV)injection into your vein, usually over 1 hour.Docetaxel Injection is usually given every 3 weeks.Your healthcare provider will decide how long you will receivetreatment with Docetaxel Injection.Your healthcare provider will check your blood cell counts andother blood tests during your treatment with Docetaxel Injectionto check for side effects of Docetaxel Injection.Your healthcare provider may stop your treatment, change thetiming of your treatment, or change the dose of your treatmentif you have certain side effects while receiving DocetaxelInjection.

See "What is the most important information I shouldknow about Docetaxel Injection?".Neurologic problems. Neurologic symptoms are common inpeople who receive Docetaxel Injection, but can be severe. Tellyour healthcare provider right away if you have numbness,tingling, or burning in your hands or feet (peripheral neuropathy)or weakness of your legs, feet, arms, or hands (motorweakness).Vision problems including blurred vision or loss of vision. Tellyour healthcare provider right away if you have any visionchanges.Docetaxel Injection contains alcohol. The alcohol content inDocetaxel Injection may impair your ability to drive or usemachinery right after receiving Docetaxel Injection. Considerwhether you should drive, operate machinery or do otherdangerous activities right after you receive Docetaxel Injectiontreatment.Tumor lysis syndrome (TLS). TLS is caused by the fastbreakdown of cancer cells. TLS can cause kidney failure, theneed for dialysis treatment, or heart problems, and may lead todeath. Your healthcare provider will do blood tests to check forTLS when you first start treatment and during treatment withDocetaxel Injection. Tell your healthcare provider right away ifyou have any symptoms of TLS during treatment with DocetaxelInjection, including:nauseavomitingconfusionshortness of breath

ooooo•

The most common side effects of Docetaxel Injectioninclude:

••

•

••••••••••••••

•

Tell your healthcare provider if you have a fast or irregular heartbeat,severe shortness of breath, dizziness or fainting during your infusion.If any of these events occurs after your infusion, get medical helpright away.Docetaxel Injection may affect fertility in males. Talk to your healthcareprovider if this is a concern for you.These are not all the possible side effects of Docetaxel Injection. Formore information ask your healthcare provider or pharmacist.Call your healthcare provider for medical advice about side effects.You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use ofDocetaxel Injection.Medicines are sometimes prescribed for purposes other than those

irregular heartbeatdark or cloudy urinereduced amount of urineunusual tirednessmuscle crampsYou may experience side effects of Docetaxel Injection that mayimpair your ability to drive, use tools, or operate machines. If thishappens, do not drive or use any tools or machines beforediscussing with your healthcare provider.

infectionslow white blood cells (help fight infections), low red blood cells(anemia), and low platelets (help blood to clot)allergic reactions (See “What is the most importantinformation I should know about Docetaxel Injection?”)changes in your sense of tasteshortness of breathconstipationdecreased appetitechanges in your fingernails or toenailsswelling of your hands, face or feetfeeling weak or tiredjoint and muscle painnausea and vomitingdiarrheamouth or lip soreshair loss: in some people, permanent hair loss has been reportedredness of the eye, excess tearingskin reactions at the site of Docetaxel Injection administrationsuch as increased skin pigmentation, redness, tenderness,swelling, warmth or dryness of the skintissue damage if Docetaxel Injection leaks out of the vein into thetissues

listed in this Patient Information. You can ask your pharmacist orhealthcare provider for information about Docetaxel Injection that iswritten for health professionals.What are the ingredients in Docetaxel Injection?Active ingredient: docetaxelInactive ingredients: alcohol, citric acid, polyethylene glycol 300,and polysorbate 80Manufactured for:Sandoz Inc.Princeton, NJ 08540Manufactured by:EBEWE Pharma Ges.m.b.H. Nfg.KGA-4866 Unterach, AustriaFor more information, call 1-800-525-8747.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: Jan 2021

Every three-week injection of Docetaxel Injection for breast, non-small celllung, and stomach, and head and neck cancersTake your oral corticosteroid medicine as your healthcare provider tellsyou.

Day 1 Date:________ Time: _____AM_____ PMDay 2 Date:________ Time: _____AM_____ PM(Docetaxel Injection Treatment Day)Day 3 Date:________ Time: _____AM_____ PM

Every three-week injection of Docetaxel Injection for prostate cancerTake your oral corticosteroid medicine as your healthcare provider tellsyou.

Date:________ Time: ________Date:________ Time: ________(Docetaxel Injection Treatment Day)Time: ________

Package/Label Principal Display PanelRx only NDC 66758-050-012 mL Multiple Dose VialDOCETAXELINJECTION

Oral corticosteroid dosing:

Oral corticosteroid dosing:

20 mg/2mL(10 mg/mL)For Intravenous Infusion OnlyReady to add to infusion solution. Check concentration prior to preparation. Seepackage insert for complete instructions.SANDOZ

Package/Label Principal Display PanelRx only NDC 66758-050-028 mL Multiple Dose VialDOCETAXELINJECTION80 mg/8mL(10 mg/mL)For Intravenous Infusion OnlyReady to add to infusion solution. Check concentration prior to preparation. Seepackage insert for complete instructionSANDOZ

Package/Label Principal Display PanelRx only NDC 66758-050-0316 mL Multiple Dose VialDOCETAXELINJECTION160 mg/16mL(10 mg/mL)For Intravenous Infusion OnlyReady to add to infusion solution. Check concentration prior to preparation. Seepackage insert for complete instructions.SANDOZ

Sandoz Inc.

DOCETAXEL docetaxel injection, solution

Product InformationProduct Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:66758-050

Route of Administration INTRAVENOUS

Active Ingredient/Active MoietyIngredient Name Basis of Strength Strength

DOCETAXEL (UNII: 15H5577CQD) (DOCETAXEL ANHYDROUS -UNII:699121PHCA)

DOCETAXELANHYDROUS

10 mg in 1 mL

Inactive IngredientsIngredient Name Strength

POLYSORBATE 80 (UNII: 6OZP39ZG8H) 80 mg in 1 mLALCOHOL (UNII: 3K9958V90M) 275.9 mg in 1 mLPOLYETHYLENE GLYCOL 300 (UNII: 5655G9Y8AQ) 648 mg in 1 mLCITRIC ACID MONOHYDRATE (UNII: 2968PHW8QP) 4 mg in 1 mL

Packaging# Item Code Package Description Marketing Start

DateMarketing End

Date1 NDC:66758-

050-01 1 in 1 CARTON 06/29/2011

1 2 mL in 1 VIAL, MULTI-DOSE; Type 0: Not aCombination Product

2 NDC:66758-050-02 1 in 1 CARTON 06/29/2011

2 8 mL in 1 VIAL, MULTI-DOSE; Type 0: Not aCombination Product

3 NDC:66758-050-03 1 in 1 CARTON 06/29/2011

3 16 mL in 1 VIAL, MULTI-DOSE; Type 0: Not aCombination Product

Marketing InformationMarketingCategory

Application Number or MonographCitation

Marketing StartDate

Marketing EndDate

NDA NDA201525 06/29/2011

Labeler - Sandoz Inc. (005387188)

Revised: 1/2021